tbuckley/cabot-search huggingface dataset:
Abstract 5611: ETS2 Contributes to a Pro-atherogenic Endothelial Cell Phenotype, Causing Plaque Destabilization in Advanced Atherosclerotic Lesions
Authors: Caroline Cheng, Dennie Tempel, Wijnand den Dekker, Remco Haasdijk, Robert Herpers, Frank Bos, Esther van de Kamp, Lau Blonden, Stefan Schulter-merker, Henricus J Duckers
Journal: Circulation (2009)

Neovascularization is a requirement for embryonic development and plays an important role in the pathogenesis of various diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. Previously, we conducted a genome-wide microarray analysis for vasculogenesis during murine embryonic development. The E 26 T ransformation-specific S equence 2 (ETS2) transcription factor was upregulated in Flk1+ angioblasts and vascular expression of ETS2 was validated by whole mount in situ hybridization in the developing zebrafish. We sought to assess the role of ETS2 on neovascularization during atherosclerotic lesion progression toward plaque instability. We conducted experiments in ApoE−/− mice using a vulnerable plaque (VP) model that creates vulnerable and stable plaques in the common carotid artery by flow alteration. QPCR analysis showed that ETS2 expression is augmented in vulnerable versus stable lesions (P&lt;0,05, N=3). Stimulation with the pro-atherogenic cytokine TNF α increased ETS2 expression and induced ETS2 translocation from the golgi area to the nucleus. Western Diet increased ETS2 expression on the endothelium of the aorta of ApoE−/− animals compared with chow-fed controls, indicated by whole mount staining (P&lt;0,05, N=4). In vitro knockdown of ETS2 by SiRNA in HUVECs diminished the expression of the cytokines MCP1, IL6, and the adhesion molecule VCAM1, under basal conditions and in response to TNF α (P&lt;0,05, N=4). ETS2 knockdown by SiRNA impeded new vessel formation in a matrigel tube-formation assay (P&lt;0,05, N=8). In vivo , adenoviral transduction of ETS2 in the adventitia of the VP region significantly augmented the vascular network of the adventitia compared with shamvirus treated controls. ETS2 overexpression increased both lesion size and necrotic core area, and promoted plaque destabilization by increasing intraplaque lipid and macrophage accumulation, while vascular smooth muscle cell accumulation was diminished. In conclusion, ETS2 expression correlates with plaque instability and responds to pro-atherogenic stimuli. Subsequently, ETS2 function is crucial for induction of the pro-atherogenic EC phenotype and promotes destabilization in advanced atherosclerotic lesions.
Abstract 5623: Early Antithrombotic Therapy Performance Measure in Ischemic Stroke and Clinical Outcomes
Authors: Gregg C Fonarow, Eric E Smith, Matthew J Reeves, Wenqin Pan, DaiWai Olson, Adrian F Hernandez, Eric D Peterson, Lee H Schwamm
Journal: Circulation (2009)

Background: Guidelines recommend that patients hospitalized with ischemic stroke should receive antithrombotic therapy within 48 hours of symptom onset to reduce stroke mortality and morbidity. An early antithrombotic process of care measure is being considered by the Center for Medicare and Medicaid Services (CMS). However, it is unknown if this process of care measure is associated with outcomes in routine clinical practice and provides discrimination of the quality of stroke care provided at the hospital level. Methods: We analyzed data from 91,184 Medicare fee-for-service beneficiaries enrolled from 625 Get With The Guidelines-Stroke hospitals between April 2003 and December 2006, which were linked to outcome data from CMS. The process measure assessed was the % of patients with ischemic stroke who received antithrombotic (antiplatelet or anticoagulant) therapy by the end of hospital day two in the absence of IV tPA and as long as no contraindications existed. Cox proportional hazards models were used to estimate the unadjusted and adjusted association of this process measure with 30-day mortality. Results: Mean age was 79.3 years, 58% were female, and 32% had prior stroke/TIA. The median hospital conformity rate was 93.8% (25 th -75 th , 90.3–96.7%) for this measure. The 30-day mortality rate (measured from hospital day 2) in this cohort was 13.1%. The adjusted odds ratio for 30-day mortality with a 10% increase in adherence at the hospital level was 0.91, 95% CI 0.87– 0.96, P=0.0005. Conclusions: An early antithrombotic therapy performance measure in eligible ischemic stroke patients is associated with improved 30-day outcomes, discriminates quality of care for ischemic stroke, and may be considered a useful clinical performance measure. This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5543: Carbon Nanotubes Allow Fluorescence Imaging of Macrophages in Mouse Carotid Atherosclerosis
Authors: Hisanori Kosuge, Masahiro Terashima, Sarah Sherlock, Toshiro Kitagawa, Hongjie Dai, Michael V McConnell
Journal: Circulation (2009)

Introduction: Macrophages are important imaging targets for characterizing and monitoring atherosclerotic lesions. Carbon nanotubes show promising properties as vehicles for cellular imaging and therapy. Methods: In vitro : mouse macrophage cells (RAW) were incubated for 24 hours with single-walled carbon nanotubes (NT; diameter 1.2nm, concentration 2.5mg/L) labeled with a near infrared fluorophore Cy5.5. NT uptake was examined using confocal microscopy. In vivo : FVB mice (N=6) had a macrophage-rich carotid atherosclerotic lesion created through high fat diet for 4 weeks and diabetes induction by 5 daily injections of streptozotocin, followed 2 weeks later by ligation of the left carotid artery (N=4) or sham operation (N=2). Two weeks post operation, all mice were given NT-Cy5.5 (8nmol of Cy5.5) via tail vein and scanned serially over 48 hours by in-vivo fluorescent imaging (CRI, Woburn, MA). Then both in situ and ex vivo imaging were performed followed by histological evaluation. Results: NT were taken up by 92% of macrophages in vitro. In vivo imaging showed limited carotid signal, however, both in situ and ex vivo imaging showed high signal from the ligated left carotid arteries (upper figure , graph). No accumulation of NT was seen in non-ligated right carotid arteries or sham-operated left carotid arteries (left carotid - yellow arrows, right carotid - red arrows). Immunofluorescence microscopy of the ligated carotid lesions (lower figure ) showed colocalization of NT-Cy5.5 and macrophages labeled with Mac3/FITC. Conclusions: NT accumulate in atherosclerotic macrophages in vivo and provide a multi-functional platform for plaque imaging and potentially therapy. This research has received full or partial funding support from the American Heart Association, Western States Affiliate (California, Nevada &amp; Utah).
Abstract 5603: LL-37 Improves Adhesion and Therapeutic Effects of Embryonic EPCs in Chronic Ischemia (Rabbit Model)
Authors: Achim Pfosser, Rabea Hinkel, Georg Stachel, Teresa Trenkwalder, Antonis Hatzopoulos, Robert Bals, Christian Kupatt
Journal: Circulation (2009)

Therapeutic neovascularization can be achieved by vascular growth factors or by mobilisation or exogenous application of endothelial progenitor cells. We could already demonstrate that murine embryonal EPCs (eEPCs) are capable of inducing therapeutic angiogenesis in a chronic hindlimb model (rabbit). Furthermore we could show that homing of these cells can be enhanced by transient overexpression of the pro-inflammatory transcription factor nfkb subunit p65. In the present study, we aimed at peptide activation of NF kappa b in the eEPC population. For this purpose, we used the cathelicidin (LL-37), which binds to the receptor FPRL1 subsequently activating NF kappa B. Methods: Adhesion of wildtype (wt), p65 transfected (p65t) and LL37-activated eEPCs (100 μ g, LL37-eEPC) was examined in vitro in flow chamber experiments. In rabbits, at d7 after femoral artery excision, 5×106 eEPCs (n=5 per group) were retroinfused into the anterior tibial vein. At d7 and 35 angiography of both hindlimbs was performed for collateral quantification and frame count score (cinedensitometry, % of d7 level each). Capillary/muscle fiber (C/MF) ratio was assessed at d35. Results: eEPC adhesion was more than doubled after pre-treatment with LL-37 (326±13 cells/field vs. 153±19, wt). In vivo, no difference was found in C/MF ratio of p65t-eEPC- or wt-eEPC-treatment (1,44±0.10 vs. 1.41±0.09, respectively), whereas LL-37-eEPC treated animals showed a significant effect (1,93±0,13). Collateral growth (wt-eEPCs 129±5% vs. 109±4% in controls), was elevated by p65t-eEPCs (146±4%), and further increased in LL37-ePCs (179±8%). The wt-eEPC-induced gain of perfusion (151±5% vs. 109±10% in controls) was similarly improved by p65t-eEPC transfusion (205±24%) and LL-37-preincubation (244±22%). We conclude that induction of a pro-inflammatory phenotype in eEPCs by either transient p65 transfection or LL37 enhances recruitment and subsequent neovascularization in ischemic tissue.
Abstract 5563: Pioglitazone Improves Endothelium-Dependent Vasodilation in Hypertensive Patients With Impaired Glucose Tolerance Through a Decrease in Oxidative Stress
Authors: Hidaka Takayuki, Yukihito Higashi, Junko Soga, Yuichi Fuii, Takaki Hata, Naomi Idei, Noritaka Fujimura, Masao Yohsizumi, Yasuki Kihara
Journal: Circulation (2009)

Objective : The aim of this study was to determine long-term pioglitazone treatment restores endothelial function in hypertensive patients with impaired glucose tolerance (IGT) and to elucidate the roles of oxidative stress and insulin resistance in endothelial function/ Research Design and Methods : We evaluated the effects of pioglitazone treatment for 12 weeks on forearm blood flow (FBF) responses to acetylcholine (Ach), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, in 34 hypertensive patients with IGT who were randomly divided into a pioglitazone group (n=17) and a conventional therapygroup (control group) (n=17) and in 34 age- and gender-matched healthy subjects. FBF was measured by using a strain-gauge plethysmography. Results : FBF response to ACh was greater in healthy subjects than in hypertensive patients with IGT, although the FBF responses to SNP were similar in the two groups. Pioglitazone increased the FBF responses to ACh from 16.3±6.8 to 23.6±7.1 mL/min per 100 mL tissue (P&lt;0.05) and decreased urinary excretion of 8-hydroxy-2′-deoxyguanosine, an indez of oxidative stress. Pioglitazone did not alter SNP-stimulated vasodilation. Administration of N G -monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the augmentation of FBF responses to ACh correlated with the decrease in urinary extretion of 8-hydroxy-2′-deoxyguanosine but not with changes in other parameters (r=−0.36, P&lt;0.01). Conclusion : These findings suggest that pioglitazone improves endothelial function in hypertensive patients with IGT through an increase in NO bioavailability by, at least in part, a decrease in oxidative stress.
Abstract 5548: Blockade of KCa3.1 Calcium-activated Potassium Channels Prevents Endothelial Inflammation
Authors: Masanori Ohta, Sandhya Nandedkar, Heike Wulff, Hanjoong Jo, Hiroto Miura
Journal: Circulation (2009)

Introduction We previously reported that blockade of the intermediate-conductance calcium-activated potassium channel (KCa3.1) prevents the development of atherosclerosis in apoE −/− mice. Endothelial cell (EC) surface CD73, ecto-5′-nucleotidase, extracellularly produces adenosine and prevents EC inflammation. Therefore we hypothesized that KCa3.1 blockade suppresses EC inflammation by upregulating CD73. Methods Human coronary artery ECs were preconditioned by 24-hour exposure to laminar shear stress (LS; 15 dyn/cm 2 ), and were treated with tumor necrosis factor- α (TNF- α , 1 ng/ml) for an additional 4 hours under LS in the presence or absence of the KCa3.1 blocker TRAM-34 (100 nM) or the KCa2.3 blocker apamin (100 nM). Expression of KCa3.1, KCa2.3, CD73 and vascular cell adhesion molecule-1 (VCAM-1) transcripts was determined by real-time PCR. Results Preconditioning ECs with LS resulted in increased KCa3.1 and KCa2.3 expression (6.6±1.8 and 3.3±0.4 fold increase vs. static condition, p&lt;0.05, n=4 –10, respectively). The LS preconditioning also increased CD73 expression (2.4±0.7 fold p&lt;0.05, n=4 –10), whereas it decreased VCAM-1 expression (0.6±0.2 fold, p&lt;0.05, n=7). TNF- α increased VCAM-1 expression (23.5±3.2 fold, p&lt;0.001) with no change in CD73 expression (1.0±0.3 fold, p=ns) under static conditions. LS decreased TNF- α -induced increase in VCAM-1 expression and increased CD73 expression (17.0±1.1 and 1.9±0.5 fold, n=4, respectively). Addition of TRAM-34 enhanced the LS-induced changes in VCAM-1 and CD73 expressions with markedly lower VCAM-1 (9.0±3.0 fold, p&lt;0.05 vs static + TNF- α ) and much higher CD73 expression (3.1±1.0 fold). In contrast, addition of apamin markedly exaggerated the VCAM-1 expression, while it increased CD73 expression as much as TRAM-34 did. Conclusions KCa3.1 blockade suppresses TNF- α -induced EC inflammation by increasing CD73 expression and decreasing VCAM-1 expression. EC KCa3.1 might therefore be one of the targets of anti-atherosclerosis therapy with KCa3.1 blockers.
Abstract 5608: Recognition of Abnormal Glucose Metabolism and Its Impact on Treatment in Patients With Acute Myocardial Infarction in Germany: Results of the SWEETHEART Registry
Authors: Anselm K Gitt, Frank Towae, Claus Juenger, Uwe Zeymer, Ralf Zahn, Jochen Senges
Journal: Circulation (2009)

Background: Recent reports from epidemiological studies demonstrated a high prevalence of undiagnosed diabetes in patients with coronary artery disease. These findings led to joint guidelines by the ESC and the EASD on diabetes, pre-diabetes and cardiovascular disease. Methods: Since 2007, 1,773 consecutive patients with STEMI or NSTEMI were enrolled into the MI-registry SWEETHEART to document patients’ characteristics and treatment in clinical practice with special emphasis on the identification of abnormal glucose metabolism. In patients with previously unknown diabetes, oral glucose tolerance test was performed at day 4 after the acute MI. We examined the prevalence of abnormal glucose metabolism and its impact on treatment in clinical practice. Results: Out of 1,773 consecutive patients with MI, 919 (52.3%) presented with STEMI and 837 (47.7%) with NSTEMI. Diabetes was already known in 33.0% of patients. Oral glucose tolerance tests identified another 16.1% of patients with manifest diabetes and 22.4% with impaired fasting glucose or impaired glucose tolerance (pre-diabetes). Only 28.5% of the MI population had no signs of abnormal glucose tolerance. Medical treatment for secondary prevention at discharge was quite well according to guidelines for antiplatelet therapy, betablockers, statins, ACE-inhibitors and ARB for all patients. Nevertheless, only 61.1% of patients with newly diagnosed diabetes did receive treatment for diabetes at discharge, in whom 74.0% only received diet. Conclusion: There was a high prevalence of newly diagnosed diabetes and pre-diabetes in consecutive patients with myocardial infarction in Germany. Despite new guidelines by the ESC and the EASD with clear recommendations for early and aggressive therapy of diabetes in patients with cardiovascular disease, 40% of myocardial infarction patients with newly diagnosed diabetes did not receive diet or an antidiabetic treatment at discharge.
Abstract 5620: Relationship Between Stroke Risk (CHADS <sub>2</sub> Score) and C-reactive Protein in Patients With Non- Rheumatic Atrial Fibrillation
Authors: Tomoko Maehama, Hiroyuki Okura, Koichiro Imai, Kikuko Obase, Yoshinori Miyamoto, Ken Saito, Akihiro Hayashida, Yoji Neishi, Takahiro Kawamoto, Kiyoshi Yoshida
Journal: Circulation (2009)

Background- CHADS 2 score is used for the stroke risk stratification in patients with atrial fibrillation (AF). Although C-reactive protein (CRP) has been shown as a possible correlate of left atrial (LA) thrombus formation in patients with non-rheumatic AF (NRAF), the relationship between CHADS 2 score and CRP is unclear. Methods- A total of 165 patients with NRAF (105 male, age 71±10 years) who underwent transesophageal echocardiography (TEE) were enrolled and analyzed. Patients with prosthetic valve, aortic dissection and infectious disease were excluded from this study. The CHADS 2 score was calculated based on a presence or absence of risk factors ( C ongestive heart failure, H ypertension, A ge≥75years, D iabetes mellitus, S troke or transient ischemic attack) as reported previously. Based on the CHADS 2 score, study patients were grouped into low (0 to 1 score), moderate (2 to 3 score) and high (4 to 6 score) risk categories. Results- Patients at low risk had significantly lower CRP levels than those at moderate or high risk (Low: 0.27±0.46 vs. Moderate: 0.40±0.56 vs. High: 0.93±0.85mg/dl, p&lt;0.01). As expected, incidence of LA spontaneous echo contrast and LA thrombus by TEE increased with increasing CHADS 2 score. Conclusion- In patients with NRAF, CHADS 2 score is related to CRP and LA thrombus formation.
Abstract 5632: Cardiac Repair Following Myocardial Injury is Mediated by Notch1 Signaling in Mesenchymal Stem Cells
Authors: Yuxin Li, Yukio Hiroi, Souen Ngoy, Hongwei Wang, Ryuji Okamoto, Kensuke Noma, Chao-Yung Wang, Qian Zhou, Ronglih Liao, James K Liao
Journal: Circulation (2009)

Background: Notch receptors regulate binary cell fate determination and are critical for embryonic development. In particular, Notch1 regulates the fate of cardiac progenitor cells and is an important mediator of vasculogenesis. However, it is little known whether Notch1 could contribute to the cardiac repair process following myocardial injury. Methods and Results: We generated mutant mice with cardiac-specific deletion of Notch1 ( α MHC-Cre/Notch1 flox/flox mice, C-N1−/−). After left descending artery (LAD) ligation, infarct size, cardiac dimension, and heart function were similar between C-N1−/− mice and control mice. However, global heterozygous Notch1 (N1+/−) mice exhibited larger infarct size, greater LV dimension, and worsening LV function compared to that of WT mice. These findings suggest that non-cardiac Notch1 contributes to cardiac repair. When the bone marrow (BM) of N1+/− mice was transplanted into WT mice, infarct size, and impaired heart function were greater, vascularity in the infarct border area was reduced, compared to WT mice transplanted with WT BM. Alternatively, WT BM transplantation (BMT) could rescue the increased myocardial injury observed in N1+/− mice. Using GFP labeled BM cell, we found more mesenchymal stem cells (MSCs) from WT BM could be recruited to the heart compared to that of N1+/− BM. Notch1 deficient also prevent the differentiation of BM-derived cells into vascular cells. In vitro, compared to WT MSCs, N1+/− MSCs showed less migration and proliferative capacity. When N1+/− MSCs were intramyocardially injected into the infarct heart of WT mice, infarct size was greater and blood vessel density was reduced compared that of WT MSCs. Indeed, N1+/− MSCs showed decreased survival after injection compared to WT MSCs. Furthermore, the expression of Notch1 target genes, Hey1 and HeyL, and cytokine receptors CSF3R and CXCR4 were reduced in N1+/− MSCs. This decrease was reversed by overexpression of Notch1 intracellular domain. Conclusions: These findings indicate that Notch signaling in MSC is critical for cardiac repair after myocardial infarction, and suggest that therapeutic strategies that increase Notch1 signaling in MSC could have clinical benefits in patients with ischemic heart disease.
Abstract 5576: Nitro-fatty Acids Reduce Atherosclerosis in ApoE Deficient Mice
Authors: Tanja K Rudolph, Volker Rudolph, Martin M Edreira, Marsha Cole, Gustavo Bonacci, Francisco J Schopfer, Steven R Woodcock, Alison Groeger, Nicholas K Khoo, Bruce A Freeman
Journal: Circulation (2009)

Objective Inflammatory processes and foam cell formation are key determinants in atherosclerosis. Electrophilic nitro-fatty acid derivatives, endogenously generated by nitric oxide- and nitrite-dependent redox reactions, mediate potent anti-inflammatory signaling actions via both receptor-dependent pathways and posttranslational modification. In vitro evidence supports that nitro-fatty acids inhibit vascular inflammatory signaling, but their in vivo actions in murine models of vascular disease remains to be elucidated. Methods and Results Herein, we demonstrate that subcutaneous administration of nitro-oleic acid (OA-NO 2 ) to apolipoprotein E deficient mice as compared to vehicle or oleic acid (OA) potently reduced atherosclerotic lesion formation in the aortic valve area (lesion area OA-NO 2 : 0.37±0.03 mm 2 ; vehicle: 0.54±0.02 mm 2 ; OA: 0.57±0.01 mm 2 ; p&lt;0.001) as well as in the entire aorta (% of atherosclerotic surface area: OA-NO 2 : 11.3±2.5%; vehicle: 18.5±2.6%; OA: 21.1±3.5%; p&lt;0.001). Immunostaining and gene expression analyses revealed that OA-NO 2 significantly inhibited adhesion molecule expression (VCAM and ICAM) and decreased infiltration of inflammatory cells (% of monocyte/macrophage positive area: OA-NO 2 : 23.9±4.3%; vehicle: 48.0±2.0%; OA: 45.7±1.5%; p&lt;0.001; number of neutrophils/field: OA-NO 2 : 10.8±4.8; vehicle: 45.3±3.9; OA: 41.5±3.4; p&lt;0.001). Both in vitro and in vivo models showed that OA-NO 2 reduced foam cell formation by attenuating oxidized LDL induced phosphorylation of signal transducer and activator of transcription-1 (STAT-1), a transcription factor recently linked to foam cell formation in atherosclerotic plaques. In addition, atherosclerotic lesions of OA-NO 2 -treated mice had a higher content of collagen (% of trichrome positive area: OA-NO 2 : 34.3±2.6%; vehicle: 18.3±2.1%; OA: 20.5±2.7%; p&lt;0.001) and α -smooth muscle actin (% of α -SMA positive area: OA-NO 2 : 24.0±3.0%; vehicle: 11.4±0.7%; OA: 11.9±0.6%; p&lt;0.001), suggesting greater plaque stability. Nitro-fatty acids did not influence metabolic profile. Conclusions These results reveal a promising therapeutic benefit in the treatment or prevention of atherosclerosis by supplementing endogenously occurring nitro-fatty acid.