tbuckley/cabot-search huggingface dataset:
Abstract 5820: Impact of Renal Function on Coronary Plaque Composition at Angiographically Severe Lesions
Authors: Motohiro Miyagi, Hideki Ishii, Ryuichiro Murakami, Satoshi Isobe, Mutsuharu Hayashi, Kosuke Arai, Tatsuaki Matsubara, Toyoaki Murohara
Journal: Circulation (2009)

Background: Recent studies have demonstrated that patients with chronic kidney disease are at high risk of arteriosclerosis. Recently, coronary plaque components can be evaluated by integrated-backscatter intravascular ultrasound (IB-IVUS) and lipid-rich plaque is associated with vulnerable plaque. Objective: The aim of this study was to investigate the relationship between renal function and tissue characterization of coronary plaque at the target stenotic site for percutaneous coronary intervention (PCI). Methods: We prospectively performed IB-IVUS before elective PCI to 89 consecutive patients with stable angina. According to estimated glomerular filtration rate (eGFR), they were divided into the two groups (eGFR &lt; 60 ml/min/1.73m 2 or eGFR ≥ 60 ml/min/1.73m 2 ). The tissue characteristics of the coronary plaque at each target stenotic site were evaluated by three-dimensional IB-IVUS just before PCI procedure. Results: Patients with eGFR &lt; 60 ml/min/1.73m 2 had greater lipid volume and smaller fibrous volume compared to patients with eGFR ≥ 60 ml/min/1.73m 2 on the 3-D IB-IVUS image (36.7±10.6 % vs. 28.7±9.3 %, p &lt; 0.001 and 59.1±8.7 % vs. 66.3±8.3 %, p &lt; 0.001, respectively). eGFR showed a significant negative correlation with lipid volume and had a significant positive correlation with fibrous volume in coronary plaques (r = −0.44, p &lt; 0.001, and r = 0.46, p &lt;0.001, respectively). Conclusion: These data suggest that there is a progressive increase in lipid-rich plaque as renal function deteriorated. Our findings may explain the increasing risk of cardiovascular events in patients with renal dysfunction.
Abstract 5805: Adenosine Down-Regulates Soluble Vascular Endothelial Growth Factor Receptor-1
Authors: Frédérique Léonard, Isabelle Ernens, Mélanie Vausort, Magali Rolland-Turner, Yvan Devaux, Daniel R Wagner
Journal: Circulation (2009)

Background: The cardioprotective nucleoside adenosine acts through 4 types of receptors: A1, A2a, A2b, A3. An emerging concept is that adenosine is a major factor driving angiogenesis, thus contributing to the repair of the ischemic heart. Angiogenesis is controlled by a plethora of vasculogenic factors, among which Vascular Endothelial Growth Factor (VEGF) and its receptor VEGFR1 (or Flt-1). A soluble form of VEGFR1 (sFlt-1) traps circulating VEGF, thereby preventing its binding to VEGF receptors. Both VEGF and sFlt-1 are induced by Hypoxia Inducible Factor 1 α . The aim of the present study was to characterize the effect of adenosine on the production sFlt-1. Methods: Primary blood monocytes obtained from healthy volunteers and patients with acute myocardial infarction (MI) were differentiated to macrophages in vitro. Treatments included: adenosine (10 μ M), CGS21680 (A2a receptor agonist, 0.1–10 μ M), SCH58261 (A2a receptor antagonist, 0.1–10 μ M), and/or LPS (100 ng/mL). ELISA, immuno-blotting and TransAM™ assay were used to measure expression levels and activation of sFlt-1 and HIF-1 α . In vitro formation of microtubules by human coronary artery endothelial cells (HCAEC) was used to evaluate angiogenesis. Results: LPS induced sFlt-1 production by macrophages from healthy volunteers and adenosine inhibited this induction (43% decrease, P=0.006, n=12). This inhibition was replicated by the A2a agonist and reversed by the A2a antagonist. The formation of a network of microtubules by HCAEC was enhanced in the presence of conditioned medium from adenosine-treated macrophages and impaired by exogenous sFlt-1. Adenosine inhibited the LPS-induced nuclear translocation of HIF-1 α , thereby preventing its activation. The effect of adenosine was replicated in macrophages isolated from acute MI patients. Conclusion: We show here for the first time that adenosine down-regulates the production of sFlt-1. This mechanism involves the adenosine A2a receptor and the transcriptional activator HIF-1 α . Our data suggest that this effect of adenosine may play a significant role in angiogenesis.
2009 James B. Herrick Award and Lecture—Clinical Research at the Crossroads
Authors: Robert O. Bonow
Journal: Circulation (2009)

Cardiovascular clinical research is experiencing unprecedented pressures in funding and manpower at a time when there are also unprecedented needs to expand the cardiovascular portfolio in translational research, outcomes research, and comparative effectiveness research. The clinical cardiovascular investigator is literally experiencing the best of times and the worst of times. Funding for the NIH, which increased at an annual rate of 15% during the years of doubling of the NIH budget from 1998 to 2003, has been essentially flat since 2003. NHLBI pay-lines for RO1 applications, which peaked at 35% in 2001, have steadily declined to 15%. The average age at which investigators receive their first NIH grant is 43 years, and in 2004, 44% of NIH awardees were over the age of 50 years. The deceleration of research funding, along with the real or perceived challenges facing young investigators in obtaining mentorship and funding, has had a chilling effect on attracting the brightest aspirants to pursue careers in clinical investigation. Simultaneously, junior cardiology faculty face increasing demands for clinical RVU productivity by their institutions because of shrinking reimbursement for clinical care, which often pushes them into private practice. These pressures are mounting at a time when there are pressing needs for clinical investigators to confront the continuing global epidemic of cardiovascular disease, which can only be overcome by innovative advances in translational, outcomes, and comparative-effectiveness research. The two highest priorities for comparative-effectiveness research in the 2009 Institute of Medicine report were studies in healthcare delivery systems and cardiovascular disease. Through the collective scientific and advocacy efforts of all of us in the community of science and medicine, these remarkable challenges can be overcome.
Abstract 5819: Long-term Existence of the Autoantibodies Against the Second Extracellular Loop of <i>β</i> 1-Adrenoceptor Induces Kidney Injury in Rats
Authors: Jingyi Liu, Lin Zuo, Ke Wang, Jihua Ma, Haijun Bao, Jue Tian, Li Yan, Huirong Liu
Journal: Circulation (2009)

Background: The effects of antibodies against the second extracellular loop (EC II ) of β 1 -adrenoceptors ( β 1 -AA) have been extensive investigated in cardiovascular disease. Our previous study has demonstrated that peritoneal exudate had been induced after long-term active immunization with synthetic peptides corresponding to human β 1 -AR-EC II in rats. We hypothesis that β 1 -AA may also bind with β 1 -AR in kidney and display pathophysiological roles. Methods: Immunization models were set up using either the peptides corresponding to the EC II of β 1 -adrenoceptors or β 1 -AA in Rats; the long-term effects of anti- β 1 -AR-EC II on kidney structure and function were observed. Results: Compared with the vehicle group, blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA) increased, and the BUN-to-CR ratio decreased markedly at the 8 th week after immunization with peptides (BUN: 8.9±0.95 mM vs 6.7±0.35 mM, P &lt;0.05; CR: 70.0±3.85 mM vs 40.9±1.38 mM, P &lt;0.01; UA: 235.6±16.43 mM vs 89.5±9.80 mM, P &lt;0.01; BUN/CR: 0.11±0.008 vs 0.16±0.008, P &lt;0.01). At the 28 th week after immunization, BUN and CR were still higher than those in the vehicle group ( P &lt;0.05, P &lt;0.01); BUN/CR was also lower than the vehicle group ( P &lt;0.05). HE and Masson’s staining revealed some mononuclear cell infiltration around the renal glomerulus, and collagen fibers accumulation around the renal tubules in 9 rats. To exclude the possible toxic role of antigen peptides to kidney in active immunization, passive immunization model by injection of purified β 1 -AA was used to confirm the above results. BUN, CR, UA significantly increased, and BUN/CR decreased as comparing with the negative sera group at 24 th week after immunization (BUN: 9.25±0.43 mM vs 6.56±0.28 mM; CR: 68.8±8.05 mM vs 41.8±1.39 mM; UA: 166.5±21.14 mM vs 86.3±12.35 mM; BUN/CR: 0.14±0.009 vs 0.16±0.006; all P &lt;0.01). The morphological changes after passive immunization by HE or Masson’s staining is consistent with the results of active immunization. Conclusion: Anti- β 1 -AA could lead impairment of kidney function and structure, suggesting that anti- β 1 -AA may have a broad spectrum of organ injury effect in addition to its reported harmful effects in cardiovascular system.
Left Ventricular Hypertrophy Patterns and the Incidence of Heart Failure: The Framingham Heart Study
Authors: Raghava S Velagaleti
Journal: Circulation (2009)

Abstract #898 Raghava S Velagaleti, Michael J Pencina, Framingham Heart Study - NHLBI, Framingham, MA; Jayashri Aragam, Veterans Admin Hosp, West Roxbury, MA; Thomas J Wang, Daniel Levy, Ralph B D’Agostino, William B Kannel, Emelia J Benjamin, Ramachandran S Vasan, Framingham Heart Study - NHLBI, Framingham, MA
2009 Charles T. Dotter Memorial Lecture—Cardiovascular Molecular Imaging of Gene and Cell Therapies
Authors: Sanjiv Gambhir
Journal: Circulation (2009)

Regenerative medicine with the use of stem cells has appeared as a potential therapeutic alternative for many disease states. Numerous questions remain with regard to the viability and biology of transplanted stem cells in the living subject. Recent advances in molecular biology and imaging have allowed the successful noninvasive monitoring of transplanted stem cells in the living subject. I will review the different imaging strategies that can be adopted to study the viability and biology of transplanted stem cells. These include the use of multimodality reporter gene imaging (eg, fusion reporters), including clinical translation of such strategies. Use of these strategies will be critical as the different regenerative therapies are being tested for clinical use.
Abstract 5679: The Critical Role of p90 Ribosomal S6 Kinase (p90RSK) in Endothelial eNOS Expression is Mediated by ERK5 Transactivation via Its SUMOylation and Phosphorylation
Authors: Nhat tu LE, Hakjoo Lee, Kyung-Sun Heo, Chang-Hoon Woo, Patrizia Nigro, Carolyn McClain, Thomas Spangenberg, Tamlyn Thomas, Bradford Berk, Keigi Fujiwara, Jun-Ichi Abe
Journal: Circulation (2009)

Emerging evidence shows the reduction of vascular reactivity in diabetic patients. We have reported that advanced glycated end products and reactive oxygen species inhibit laminar steady flow (s-flow) mediated-eNOS expression in endothelial cells (EC) via ERK5-SUMOylation, which subsequently inhibits ERK5 and KLF2 transactivation. However, it remains unknown how ERK5-SUMOylation is regulated in EC. In this study we investigated the involvement of redox sensitive kinase p90RSK on ERK5 activation and eNOS induction. Inhibition of ERK5 transactivation by H 2 O 2 was reversed by dominant negative p90RSK (21±7%-increase compared with H 2 O 2 treated cells, p&lt;0.05), indicating that this inhibition is p90RSK-dependent. Transduction of an adenovirus vector expressing DN-p90RSK (Ad-DN-p90RSK) abolished H 2 O 2 -mediated inhibition of s-flow-mediated eNOS expression. Ad-DN-p90RSK significantly inhibited H 2 O 2 -mediated ERK5-SUMOylation, suggesting that p90RSK inhibits ERK5 by increasing ERK5-SUMOylation. To elucidate how p90RSK increases ERK5-SUMOylation, we investigated the effect of de-SUMOylation enzyme SENP2, which contains potential p90RSK phosphorylation sites. Depletion of SENP2 by SENP2 siRNA increased ERK5-SUMOylation. Over-expression of SENP2 inhibited ERK5-SUMOylation in a dose-dependent manner, suggesting that ERK5 is a substrate for SENP2. An in vitro kinase assay revealed that active p90RSK phosphorylated SENP2, suggesting SENP2 as a novel substrate of p90RSK. In addition, H 2 O 2 induced SENP2 nuclear export, which was inhibited by Ad-DN-p90RSK. These data suggest that p90RSK inactivates SENP2 by phosphorylating it, thus increasing ERK5-SUMOylation and decreasing ERK5/KLF2 transactivation and eNOS expression. En face confocal microscopy of normal mouse aorta showed p90RSK localization in the perinuclear region in EC. Interestingly, while p-p90RSK exhibited nuclear localization in s-flow areas, p-p90RSK localized in the cytoplasm of EC in disturbed flow (d-flow) areas which are prone to atherosclerosis. ApoE −/− mice revealed increased p90RSK activation in d-flow areas and early atherosclerotic lesions, also supporting the patho-physiological role of the p90RSK-SENP2 axis on EC dysfunction. This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5673: Engagement of the Sphingosine 1 Phosphate Receptor 1 Induces Macrophage Egression From Atherosclerotic Lesions in Apolipoprotein E Deficient Mice
Authors: Jan Larmann, Anik Westermann, Martina Schmitz, Volker Brinkmann, Christoph Bremer, Jerzy-Roch Nofer, Gregor Theilmeier
Journal: Circulation (2009)

Background: The regulation of macrophage (MØ) and T-cell content is crucial to atherosclerotic plaque stability. MØ have the potential to rapidly egress from plaques. Sphingosine 1-Phosphate (S1P) - an integral component of high density lipoproteins (HDL) - reduces leukocyte counts at sites of inflammation. We here tested if short-term treatment with the synthetic S1P analogue FTY720 or the selective S1P receptor 1 (S1P1) agonist AUY954 affects MØ and T-cells in plaques of ApoE deficient (ApoE −/− ) mice. Methods: ApoE −/− and wild type (WT) mice were fed a 16wk western diet. For 3D in vivo Fluorescence-Mediated-Tomography (FMT), 5×10 6 peritoneal eGFP-MØ labeled with near infrared fluorescent dye (DiR) were given IV 2d prior to 2 or 4d FTY720 (1 μ g/gBW/d), AUY954 (10 μ g/gBW twice/d), or vehicle (CTR) treatment. Baseline MØ content was assessed by FMT in a region of interest covering aortic-valve and -arch. On d2 and 4 MØ influx and egress from plaques into the blood were quantified. MØ egress into aortic lymphnodes (LN) was quantified by flow cytometry. T-cell (Thy1.2), MØ (CD68) and lipid content (Oil Red O) were assessed in plaques. Results: FMT revealed net MØ recruitment during 2 days in CTR (487±151%, d2 vs. d0, p&lt;0.05, n=9) but in neither treatment group (FTY720: 67±11.9%, AUY954: 103±26.5%, p=n.s., n=9/5). After 4 days MØ related signal was reduced consistent with MØ egress from plaques in both treatment groups (FTY720: 40±9.5%, AUY954: 38±10.5%, d4 vs. d0, p&lt;0.05, n=5) but not in CTR (14922.9%, p&lt;n.s., n=5). CD68- and Oil-Red O-pos lesion area decreased by 33% and 26% (FTY720 vs. CTR, n=8, p&lt;0.05). FTY720 but not AUY954 promoted MØ relocation into LN (FTY720: 7.21.9, AUY954: 1.270.73, CTR: 2.20.7, eGFP-MØ/10 5 cells, FTY720 vs. CTR &amp; AUY954, n=5, p&lt;0.05;). 2d treatment with FTY720 reduced plaque T-cell content (10±2.6 vs. 19±4.4 cells/mm 2 , FTY720 vs. CTR, p&lt;0.05, n=5). Conclusions: Both FTY720 and AUY954 rapidly reduce macrophage content in atherosclerotic lesions indicating S1P1 involvement in this process. However, only FTY720 induces MØ relocation into regional LN and reduces plaque T-cell content. Reducing MØ and T-cells in the plaque through engagement of various S1P receptors (FTY720) vs. S1P1 represents a valid strategy for plaque stabilization.
Abstract 5650: Interactions Between the Endogenous NO Synthase Inhibitor Asymmetric Dimethylarginine and the Leukocyte-derived Hemoprotein Myeloperoxidase
Authors: Karsten Sydow, Eike-Christin von Leitner, Renke Maas, Anna Klinke, Edzard Schwedhelm, Jan T Kielstein, Dorothee Atzler, Denise Lau, Heimo Ehmke, Thomas Meinertz, Stephan Willems, Rainer H Böger, Stephan Baldus
Journal: Circulation (2009)

Background: ADMA and the NO oxidizing leukocyte-derived hemoprotein MPO are associated with cardiovascular diseases. ADMA and MPO per se coincide with increased oxidative stress and induction of inflammatory responses. Furthermore, the enzymes responsible for ADMA homeostasis (i.e. dimethylarginine dimethylaminohydrolase, DDAH) are regulated in a redox-sensitive fashion. Therefore, the aim of the study was to investigate whether there is an interaction between ADMA and MPO resulting in increased leukocyte (PMN) activation and reduced NO bioavailability. Methods: To test a direct leukocyte activating effect of ADMA, isolated human PMN were subjected to ADMA, SDMA, and fMLP -an inductor of NADPH oxidase activity- to determine PMN degranulation (MPO activity, MPO and elastase levels) and leukocyte superoxide production. NO synthase and DDAH activity was measured by GC-MS and LC-MS/MS, respectively. In vivo, the effect of chronic ADMA (250 μ mol/kg/d; 28 days) treatment on MPO concentrations was induced by osmotic minipumps in C57 mice. To test the effect of MPO on DDAH1 and -2 gene expression, taqman rtPCR technique was performed in liver and kidney tissue of MPO knockout mice. The effect of MPO on DDAH activity in vitro was studied using a recombinant DDAH enzyme. Results: ADMA and fMLP incubation -but not SDMA- significantly increased superoxide production, PMN degranulation and MPO release. Furthermore, ADMA but not SDMA was able to impair NO synthesis of PMN and enhanced PMN’s adhesion to cultured HUVECs in vitro. In vivo, chronic treatment with ADMA resulted in a significant increase of plasma MPO concentrations in C57 mice in contrast to vehicle-treated controls. DDAH1 gene expression was markedly increased in liver and kidney tissue of MPO knockout mice compared to C57 controls. In vitro, MPO and its product HOCl were able to impair recombinant DDAH activity, whereas inactivated MPO was not. Summary and conclusions: ADMA profoundly activates PMN resulting in increased degranulation and MPO release, superoxide production, and impaired NO synthesis. MPO modulates DDAH expression and impairs DDAH activity. Our data revealed a two-way interaction between the ADMA and MPO pathway, which may open a new avenue for treatment of cardiovascular disease.
Abstract 5675: Local Gene Silencing of TLR4 Expression <i>in vivo</i> Improves Vein Graft Patency in Mice
Authors: Jacco Karper, Margreet de Vries, Ben van den Brand, Hans Niessen, Imo Hoeffer, Paul Quax
Journal: Circulation (2009)

Introduction: Patency of vein grafts is limited by vascular remodelling processes such as neointima formation and accelerated atherosclerosis. Toll Like Receptor 4 (TLR4) is associated with neointima formation and atherosclerosis. Hypothesis: We hypothesize that TLR4 can serve as a local therapeutic target against vein graft disease. Methods: In human saphenous veins (huSV) immunohistochemical staining for TLR4 was performed on cross-sections of either directly harvested huSV (n=6), in vitro perfused huSV (n=6) and coronary graft huSV derived at autopsy (n=5). Mouse venous bypass grafting was performed in Balb/c mice (n=8) and in TLR4 deficient (C3H/Hej) mice (n=7) using a venous interposition model in the carotid artery. Five lentiviral TLR4 shRNAs were created and validated for local TLR4 gene silencing by measurement of murine TLR4/MD2 expression by FACS analysis and the best vector was selected for in vivo analysis. To test the effect of local TLR4 deficiency on vein graft disease virus was administered in pluronic gel and lubricated around vein grafts after vein grafting in APOE3*Leiden mice fed a high cholesterolemic diet. Results: A marked induction of focal TLR4 expression was observed in HuSV, reperfused ex vivo with whole blood under pulsatile arterial pressure. Moreover, TLR4 was abundantly present in the neointima formed in autopsy grafts and preexisting intimal lesions in directly harvested huSV. Vein grafts in C3H/Hej mice had 48±12% less vessel wall thickening (p=0.04) than Balb/c controls, 28 days after surgery. Hypercholesterolemic APOE3*Leiden mice showed massive vein graft disease due to neointima formation and accelerated atherosclerosis after vein grafting. Local gene silencing of TLR4 led to a significant reduction of vessel wall thickening (38±10%, n=10, p=0.03) in the graft segment and superior graft patency (p=0.013) as compared to the control. In conclusion, the upregulation of TLR4 expression in huSV during remodelling, the reduced vein graft thickening in TLR deficient C3H/Hej mice and reduction of vessel wall thickening after local interfering in the TLR4 pathway indicate the potential of TLR4 as a local therapeutic target against vein graft disease to increase graft patency.
Abstract 5655: Autoantibodies Against Endothelin-1 Receptors Are Involved in the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Michael Dandel, Gerd Wallukat, Hans B Lehmkuhl, Angela Englert, Roland Hetzer
Journal: Circulation (2009)

Background In patients with pulmonary arterial hypertension (PAH) production of endothelin-1 (ET-1) is increased and elevated ET-1 plasma levels correlate with PAH severity. After repeated detection of agonistic antibodies against the ET-1 A receptor (ETA) in PAH patients’ sera we assessed their prevalence and properties. Methods Using spontaneously beating rat neonatal cardiomyocytes as bioassay we analyzed sera of PAH patients for the presence of autoantibodies (AABs) against ETA receptors. AABs were purified by affinity chromatography. Results At the time of AAB testing, the pulmonary vascular resistance (PVR) in the 58 evaluated PAH patients varied between 500 and 1920 dyn • sec • cm −5 (median 1088 dyn • sec • cm −5 ) and 45 (77.6%) were in functional NYHA/WHO class ≥ III. Of these 58 patients 44 (78.7%) tested positive for AABs against ETA receptors. ET-1 and the AABs against ETA exerted agonistic negative chronotropic effects on the neonatal cardiomyocytes (decrease in pulsation rate), which were blocked by the ETA antagonist BQ610, but not by the ET-1 B receptor blocker BQ788. The AABs induced permanent stimulation without desensitization of the receptor mediated signal cascade and the effect increases with higher AAB concentrations. First attempts to eliminate by immunoadsorption these AABs (which appeared to belong to the IgG2 subclass) in 5 PAH patients showed encouraging results. After AAB removal, which was well tolerated by all patients, at the first controls performed 3 and 6 weeks later all 5 patients showed reduction in right ventricular diameters, lower pulmonary arterial pressure, higher cardiac index and improved exercise tolerance (increase in both VO 2 max and 6 minute walk distance). In one patient the AABs reappeared after 2 months and this AAB reappearance was associated with clinical worsening and PVR increase. Conclusions The majority of patients with advanced PAH tested positive for functional serum AABs against ETA These AABs activate the receptors, like ET-1, but prevent the desensitization of the receptor-mediated signal cascade normally seen with ongoing receptor stimulation. Our results suggest that these AABs could be involved in PAH pathogenesis. AAB removal by immunoadsorption might be a possible new therapeutic approach.