tbuckley/cabot-search huggingface dataset:
Abstract 5767: Viral Anti-inflammatory Treatment of Unstable Coronary Syndromes: The VT-111 Acute Coronary Syndrome Trial
Authors: Jean-Claude Tardif, Philippe L’Allier, Jean Grégoire, Reda Ibrahim, Grant McFadden, William J Kostuk, Merril L Knudtson, Marino Labinaz, Ron Waksman, Carl J Pepine, Colin Macaulay, Alexandra Lucas
Journal: Circulation (2009)

Background: Up-regulation of inflammatory responses contributes to coronary plaque rupture, thrombosis, and vascular occlusion leading to myocardial and cerebral infarction. Some viruses have developed potent proteins that block key steps in both the innate and adaptive immune responses. VT-111 is a viral serine proteinase inhibitor that demonstrates reductions in monocyte migration to sites of vascular damage in a wide range of animal models. Methods: In a double-blind, placebo-controlled trial, the safety of VT-111 plus standard of care was evaluated in patients with acute coronary syndromes treated with stents. Patients received IV VT-111 or placebo once daily for 3 days, starting immediately before intervention. Patients were followed for 3 days in hospital, and at 14, 28 days and 3 and 6 months for safety/efficacy endpoints, including biomarker analysis and MACE (death, MI or revascularization). At 6 months, restenosis was evaluated by intravascular ultrasound. Results: Forty-eight patients were enrolled at 7 sites; 19 patients received 5 μ g/kg VT-111, 17 patients received 15 μ g/kg and 12 patients received placebo. There were no differences between the treated and control groups on key safety endpoints, including coagulation parameters and adverse events. A trend towards a decrease in MACE was observed, with a reduction to 0% in the 15 μ g/kg group from 18% in controls. A significant, dose-dependent reduction in Troponin I levels was observed with VT-111 at 8, 16, 24 and 54 hours post-dose (p&lt;0.05). Similar reductions were observed in CK-MB levels at 8, 16 and 24 hours post-dose (p&lt;0.05). Trends towards a reduction in MCP-1 were also observed. Further analysis suggests that VT-111 may also have early effects on markers such as EN-RAGE (S100A12), IL-6 and CD40L. There were no differences in in-stent plaque area or lumen area between control and treated groups, as assessed by IVUS. Conclusion: This randomized, placebo-controlled trial supports the safety of 3 daily IV injections of VT-111, a first in class viral-derived anti-inflammatory therapeutic agent. A significant reduction in biomarkers of cardiac damage demonstrates the potential of this novel class of protein therapeutics.
Abstract 5761: Anti-thrombotic and Anti-platelet Therapies for Acute Myocardial Infarction in Dialysis Patients: A Collaborative Project of the United States Renal Data System and National Registry of Myocardial Infarction
Authors: Gautam R Shroff, Paul Frederick, Charles A Herzog
Journal: Circulation (2009)

Background: Dialysis pts sustain high mortality rates from acute myocardial infarction (AMI) but were excluded from trials evaluating therapeutic strategies in AMI. Aims: To compare the utilization of anti-thrombotic (AT) and anti-platelet (AP) therapies during AMI in dialysis vs. non-dialysis pts and the relation between outcomes of dialysis pts and the use of AT and AP therapies. Methods: Retrospective cohort study using cross-matched data from the US Renal Data System database and 3rd National Registry of Myocardial Infarction for AMI hospitalizations between 04/01/1998 and 06/30/2000. A cohort of 3049 matching dialysis pts in both databases were identified; pts transferred in or out of the index hospital were excluded, leaving 2390 dialysis and 304096 non-dialysis pts for analysis. Results: Table 1 describes utilization of AT and AP therapies in dialysis pts with AMI. Table 2 details likelihood of adverse outcomes relative to the use of AT and AP agents. Conclusions: AT and AP therapies are underutilized in dialysis pts with AMI. Aspirin use is associated with marked reduction in mortality and major cardiac events in both dialysis and non-dialysis pts. In contrast to non-dialysis patients, GP IIb/IIIa antagonist use is associated with a 3 fold increase in major bleeding in dialysis pts without any reduction in risk of cardiac events; and UF and LMW heparin use are also not associated with any reduction in mortality and cardiac events. Optimal AT and AP strategies in dialysis pts need to be further examined in prospective studies.
Abstract 5580: Nanolytic Approach to Prompt Revascularization in Acute Ischemic Stroke
Authors: Jon Marsh, Hu Grace, Kirk D Wallace, Frank D Hockett, Dana R Abendschein, Patrick J Gaffney, Samuel A Wickline, Gregory M Lanza
Journal: Circulation (2009)

Background: Vascular-constrained fibrin-specific nanolytic agents could permit early revascularization in the setting of acute ischemic stroke. Development of fibrin-targeted nanolytics requires optimized surface co-presentation of homing ligands and fibrinolytic enzymes on nanoparticles without compromising bioactivity. Objective : The study optimized human urokinase coupling and anti-fibrin homing ligand density for targeted thrombolytic efficacy and demonstrated the concept in vivo. Methods and Results: Minimal thiolation (N-succinimidyl-S-acetylthioacetate, SATA) of urokinase (i.e., 1 to 3 SATA/molecule) diminished human clot dissolution time relative to the native molecule; greater degrees of thiolation (3 to 6 SATA/molecule) severely decreased activity. For dog clots, which digested slower than human clots, 1 to 3 SATA/urokinase did not further impair fibrinolysis rate. Concomitant coupling of thiolated urokinase and anti-fibrin antibody (50:5, 100:10, 200:20, and 400:40 ratio, respectively) to perfluorocarbon nanoparticles resulted in optimal clot dissolution for the 100:10 and 200:20 formulations. Increasing the surface urokinase-to-antibody ratio from 0:10 to 50:10, 100:10, 200:10, and 400:10 increased particle size from 273 nm (0:10) to 340 nm at the 50:10 and 100:10 enzyme levels, and to more than 400 nm with 200 urokinase molecules per particle. Acoustic microscopy (25MHz) was used to quantify binding of the fibrin-targeted PFC nanoparticles to acoustically transparent human clots. Fibrin targeting with 10 antibodies per particle provided minimal acoustic enhancement in comparison with the relatively increased (p&lt;0.05) but equivalent signals obtained with 20 or 40 antibodies per particle. Dissolution of canine femoral clots, created by electrical injury, was monitored with low MI ultrasound under open circulation conditions following in situ targeting with the nanolytic system. Substantial subjective clot dissolution and fragmentation was observed in three animals over 60 minutes, demonstrating the nanolytic concept. Conclusion: Nanolytic agents can target fibrinolytic enzymes to lyse nascent thrombus, which may permit early revascularization in acute ischemic stroke with minimal hemorrhagic risk.
Abstract 5584: Extra Domain A of Fibronectin (EDA) is Critically Involved in Collateral Artery Growth
Authors: Daphne Groot, Sebastian Grundmann, Dominique P.V. de Kleijn, Gerard Pasterkamp, Imo E. Hoefer
Journal: Circulation (2009)

Background Shear stress induced arterial remodeling leading to collateral artery formation (arteriogenesis) is an important protective mechanism in cardiovascular disease, redirecting blood flow around arterial stenoses. Toll Like Receptors (TLRs), part of the innate immune system, play an important role in arterial remodeling, indicating the presence of a yet unknown endogenous ligand responsible for TLR mediated arteriogenesis. Methods &amp; Results RT-PCR for endogenous TLR ligands was performed in mouse hind limb tissue after femoral artery occlusion (n=10). Hsp60 and EDA, candidate endogenous TLR-4 ligands, were significantly upregulated compared to sham operated hind limbs (EDA: occlusion 0.88 ± 0.77 versus sham 0.0096 ± 0.012 pg plasmid; HSP60: occlusion 0.0050 ± 0.0049 versus sham 0.0026 ± 0.0021 pg plasmid). To address the functional role of the increased EDA expression, EDA −/− (n=22) and corresponding wild type mice (BALB/C, n=22) were subjected to unilateral femoral artery ligation and contra lateral sham operation. Maximum hind limb perfusion restoration was assessed using fluorescent microspheres 7 days after surgery under maximal vasodilation. Perfusion restoration was significantly decreased in EDA −/− mice compared to wild type mice (EDA 22±2.6% vs. BALB/C 31±1.8% of sham operated hind limb perfusion, p=0.011), supporting a critical role of EDA during collateral artery growth. Conclusion We demonstrate that the Extra Domain A of fibronectin may be the endogenous TLR ligand critically involved in collateral development. Its expression is enhanced during collateral development while its depletion in mice attenuates perfusion restoration after acute arterial occlusion.
Abstract 5531: The Impacts of Thin-Slice Contrast-Enhanced Computed Tomography and Rapid Cortisol Measurement During Adrenal Venous Sampling
Authors: Kenji Nishioka, Hiroki Teragawa, Kenji Oki, Yuichi Fujii, Naoya Mitsuba, Takenori Fujimura, Shinsuke Mikami, Kensuke Noma, Takafumi Ishida, Yukihito Higashi, Yasuki Kihara
Journal: Circulation (2009)

Background: It has been considered that Adrenal venous sampling (AVS) is the golden standard to identify primary aldosteronism (PA). However, there have been technical difficulties in AVS, especially in right AVS. Therefore, we investigated whether the anatomical examination of adrenal vein using thin-slice contrast-enhanced computed tomography (CT) and the monitoring cortisol concentrations during catheterization affect the success rate of AVS in patients with suspected of having PA. Methods: Forty-eight patients who were suspected of having PA, were enrolled. Thin-slice contrast-enhanced CT with 1.2mm-slice and rapid cortisol assay using electro chemiluminescent Immunoassay (ECLIA) were performed in 18 patients (Group I). Contrast-enhanced CT with 5mm-slice were performed in 20 patients (Group II). Samples were collected from the vena cava as well as from right and left adrenal veins. We evaluated the procedure success rate and the total radiation time in two groups. Results: Date are expressed as the mean±SEM. The patients characteristics were similar in the two groups. On contrast-enhanced CT, right adrenal vein was detected in all patients in Group I (100%) although it was detected only 11 patients (55%) in Group II (p&lt;0.05). The success rate of AVS was significant higher in Group I (96%), than in Group II (30%, p&lt;0.0001) while the success rate of left AVS was not different in the two groups. The total radiation time was shorter in Group I (22±8 min) than Group II (32±9 min, p&lt;0.05). Conclusions: Anatomical examination using thin-slice contrast-enhanced CT and intraoperative cortisol assays increase the procedure success rate, and decrease the duration time of radiation. The rapid cortisol assay kit might be valuable and timely information for improving the success rate of adrenal venous sampling. This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5797: New Biomarkers for Assessing the Activity of Takayasu Arteritis
Authors: Takashi Ishihara, Tetsuo Kamiishi, Go Haraguchi, Mitsuaki Isobe
Journal: Circulation (2009)

Background - Takayasu arteritis (TA) is a chronic vasculitis, mainly involving the aorta and its main branches. Erythrocyte sedimentation rate (ESR) and C-reactive protein(CRP)have generally been used for monitoring the disease activity. We frequently experience patients who show inflammatory symptoms without an elevation of CRP, even though they are treated with immunosuppressants. Therefore, we sought for useful and sensitive biomarkers to diagnose subtle activity of TA. We hypothesized that pentraxin3 (PTX3) and matrix metalloproteinases (MMPs) could be biomarkers of TA to detect patients who develop recurrence of the disease even in the absence of CRP elevation. Methods and Results - Consecutive series of 45 patients with TA and 20 age-matched healthy controls were enrolled in this study. According to the clinical symptoms of the patients, 23 patients were in an active phase as evidenced by clinical recurrences within 2 years of blood sampling and 22 patients were in an inactive phase without any inflammation for more than 2 years. Circulating levels of PTX3, MMP-2, MMP-3 and MMP-9 were determined by ELISA. Patients in an active phase had significantly higher level of high sensitive CRP (hsCRP), PTX3, MMP-3 and MMP-9 than those in an inactive patients. Sensitivity (SE), specificity (SP) and area under the ROC curve (AUC) to detect active patients of each biomarker are as follows. hsCRP: SE 53.33%, SP 90.91%, AUC 0.798, PTX3: SE 76.19%, SP 76.19%, AUC 0.871. MMP-3: SE 60.87%, SP 86.36%, AUC 0.831, MMP-9: SE 61.90%, SP 66.67%, AUC 0.728. PTX3 was the best single marker with the highest diagnostic accuracy. Among 21 patients in an active phase, 9 patients showed negative hsCRP level (&lt;4837ng/ml). However, PTX3 level was elevated (&gt;5.27ng/ml) in 7 of the 9 patients. Patients with TA had significantly higher level of MMP-9 (active:360±75ng/ml, inactive:229±48ng/ml) than normal controls (23±5ng/ml) inspective of disease activity. Evaluation of MMP-9 may suggest prior existence of TA even in inactive patients. Conclusions - PTX3, MMP-3 and MMP-9 could be new and sensitive biomarkers to estimate the activity of TA. We can predict recurrence of TA by elevation of PTX3 even patients whose CRP is negative.
Abstract 5587: Id1 Regulates Angiogenesis by Determining the Specification and the Timing of Notch Signaling
Authors: Koichi Nishiyama, Satoshi Arima, Toshiyuki Ko, Yuichiro Arima, Yasunobu Uchijima, Yukiko Kurihara, Hisao Ogawa, Hiroki Kurihara
Journal: Circulation (2009)

Id1, a helix-loop-helix transcriptional factor, has emerged as a potent contributor of angiogenesis. We have previously reported that Id1 confers in vivo angiogenic property on human vascular endothelial cells (ECs) and that nucleo-cytoplasmic localization of Id1 might control angiogenesis. However, the downstream targets of Id1 and its interaction with other signaling pathways involved in angiogenesis are grossly unknown. To unveil the issue, we first examined the expression pattern of Id1 in ECs during angiogenesis in vitro and in vivo. We observed that Id1 expression levels were more prominent in sprouting ECs as compared with sheet-forming ECs at the proximal end of the sprouts in murine aortic ring assay. In the sprouts, furthermore, Id1 exhibited a mosaic expression pattern, mixed with weakly or no Id1-expressing ECs. We also identified similar expression pattern immunohistochemically in developing vessels of murine embryonic brain. Because the mosaic pattern of Id1 expression was reminiscent of Notch activation pattern in developing vessels, we next verified a possible crosstalk between Id1 and Notch signaling by RNAi-induced gene knockdown in cultured human ECs. Expectedly, siRNA-induced Id1-knockdown strikingly and specifically enhanced Notch-dependent upregulation of Hey2 (Gridlock) and to a less extent Hey1 but not Hes1. Id1-knockdown also upregulated the expression of a Notch-downstream effector Ephrin B2 in a Hey2-dependent manner. We finally examined how Id1 exhibited the mosaic expression pattern in ECs of developing vessels. Interestingly, Western blot analysis (hourly sampled for 12 hours) showed that total protein levels of Id1 appeared to oscillate periodically in cultured human ECs under confluent condition with no evident relation to cell cycle. This finding partially explains the mosaic expression pattern of Id1 during angiogenesis. Collectively, these results suggest a novel crosstalk between Id1 and Notch signaling, where Id1 might regulate the specification and the timing of Notch/Hey2 activation. We propose that the periodic expression of Id1 may be involved in the control of angiogenesis leading to proper branching morphology.
Abstract 5557: Lack of Interleukin-1 Receptor Antagonist in Inflammatory Cells Causes Spontaneous Femoral Artery Aneurysms in Mice
Authors: Kikuo Isoda, Tomiharu Niida, Harumi Kondo, Yuko Arai, Taichirou Hayase, Takehiko Kujiraoka, Manabu Kitagaki, Norio Ishigami, Takeshi Adachi, Fumitaka Ohsuzu
Journal: Circulation (2009)

Background: Arterial aneurysms represent a complex degenerative disorder involving chronic arterial wall inflammation and destructive remodeling of structural connective tissue. The relative balance of pro- and anti-inflammatory cytokines likely controls inflammation in the aneurysm wall. The interleukin (IL)-1 receptor antagonist (IL-1Ra) negatively regulates IL-1 signaling. However, the role of IL-1Ra in aneurysm is poorly understood. Methods and Results: IL-1Ra-deficient (IL-1Ra−/−) mice (backcrossed 8 generations to the B6 background) and wild-type (WT) mice did not differ with regard to systolic arterial pressure and plasma lipid levels. However, IL-1Ra−/− mice had spontaneously developed femoral artery aneurysms after 8-month-old, and both maximal vessel area and the intimal + medial area of femoral arteries in IL-1Ra−/− mice were significantly larger compared with WT mice at 9 months of age. Real-time PCR of 9-month-old IL-1Ra−/− mice revealed significantly increased mRNA levels of IL-1 β (6.6-fold, P&lt;0.05), tumor necrosis factor (TNF)- α (12.4-fold, P&lt;0.05) and matrix metaroproteinase-9 (6.0-fold, P&lt;0.01) compared with WT mice. Histological analysis revealed numerous inflammatory cells around the femoral artery aneurysm in IL-1Ra−/− mice, and elastin staining showed destruction of the internal and external elastic lamina in IL-1Ra−/− mice. Immunostaining revealed many macrophages and some CD4-positive T cells in the adventitia. Then we studied the function of macrophage and T cell. After LPS (1 μ g/ml) stimulation, IL-1Ra deficient macrophages produced much higher levels of TNF- α than those from WT mice. Furthermore TNF- α production of T cells from IL-1Ra−/− mice stimulated with anti-CD3 antibody was also higher than those from WT mice. Finally, we performed bone marrow (BM) cell transplantation. We detected femoral artery aneurysms with many inflammatory cells in the adventitia in several WT mice receiving BM cells from IL-1Ra−/− (44%) but not WT mice (0%). Conclusions: This study demonstrates that IL-1Ra-deficiency in inflammatory cells disrupts immune system homeostasis, resulting in the development of autoimmunity and inflammation. Then the inflammation causes spontaneous femoral artery aneurysms in B6 mice.
Abstract 5549: Bone Morphogenetic Protein-2 (BMP-2) and BMP-7 Act as Instructive Factors to Specify Notch Signaling Controlling Smooth Muscle Cell Phenotype
Authors: Takehisa Shimizu, Toru Tanaka, Tatsuya Iso, Keiko Kawai-Kowase, Masahiko Kurabayashi
Journal: Circulation (2009)

Background: Vascular smooth muscle cells (VSMC) exhibit phenotypic plasticity including synthetic, contractive and osteogenic phenotypes in response to environmental cue. Bone morphogetic proteins (BMPs) and Notch signaling are essential determinants of cellular identity, but their mode of action to specify SMC phenotype is poorly defined. Here we investigate the cooperation between BMPs and Notch signaling in cultured VSMC. Methods and Results: We have recently shown that overexpression of Notch1 intracellular domain (N1-ICD) in human aortic SMC (HASMC) induced expression of both SMC and osteoblast marker genes. Interestingly, BMP-2, an osteogenic BMP implicating in vascular calcification, markedly enhanced N1-ICD-induced expression of osteoblast marker genes. Consistently, ALP activity as well as matrix mineralization were also synergistically induced by Notch and BMP-2 signaling. A specific silencing using siRNA confirmed that Msx-2 was responsible for the enhanced osteogenic phenotype induced by Notch and BMP-2. Experiments using site-specific mutation constructs of Msx2 promoter and ChiP assay revealed that the Msx-2 promoter contains functional RBP-Jk-binding site at −3770, and both this site and Smad-binding site are necessary for synergistic activation of the Msx-2 gene expression by Notch and BMP-2. In contrast, BMP-7 markedly augmented N1-ICD-induced expression of SMC marker genes, whereas expression of osteoblast marker genes was unchanged. Of note, BMP-7 failed to enhance N1-ICD-induced SMC marker gene expression in cells deficient of myocardin, indicating myocardin mediates the crosstalk between Notch and BMP-7 signaling. Conclusion: These results suggest that by BMP-2 and BMP-7 play an instructive role in specifying the Notch/RBP-Jk pathway which induces either differentiated phenotype or osteogenic phenotype of SMC Collectively, this study provides, at least in part, a mechanistic basis for the “context dependency” characteristic of Notch signaling.
Abstract 5529: Excessive Inotropic Response During Exercise Reflects Cardiovascular Stiffening in Newly Diagnosed Essential Hypertensives
Authors: Dimitris Tsiachris, Costas Tsioufis, Dimitris Syrseloudis, Anastasia Mazaraki, Vanessa Tzamou, Ioannis Andrikou, Dimitris Chatzis, Christodoulos Stefanadis
Journal: Circulation (2009)

Introduction: Exaggerated blood pressure response during exercise (EBPR) is associated with high risk for worsening hypertension, while arterial stiffness and left ventricular (LV) diastolic dysfunction have both been related with adverse cardiovascular outcomes. Hypothesis: EBPR may be associated with arterial stiffness and LV diastolic dysfunction in a large cohort of hypertensives. Methods: 222 untreated non-diabetics (152 males, mean age 54 years) with stage I – II EH underwent treadmill exercise testing and were classified as hypertensives with EBPR (n=75) based on the systolic BP elevation ≥210mmHg for men and ≥190mmHg for women, at peak exercise. The remaining patients were classified as normal inotropic responders (n=147). In all subjects carotid to femoral pulse wave velocity (PWV) was measured by means of Complior SP, while LV diastolic function was estimated by pulsed Tissue Doppler Imaging (TDI), averaging diastolic mitral annular velocities (Em, Am) from 4 separate sites of measurement. Results: Hypertensives with EBPR compared to normal inotropic responders had increased 24-hour systolic BP (137.4±10 vs 134±9mmHg, p=0.013) and PP (52.6±8 vs 49±7mmHg, p=0.001), while there was no difference in terms of age, sex and body mass index. Hypertensives with EBPR exhibited also greater relative wall thickness (0.47±0.06 vs 0.44±0.07, p=0.014), E/Em (9.45±3.1 vs 8.35±3.3, p=0.034) and PWV (9.1±1.6 vs 8.5±1.3m/s, p=0.007), as well as significantly lower values of Em (8.5±2.5 vs 9.4±2.9cm/s, p=0.046), while they did not differ in LV mass index and transmitral flow Doppler parameters (p=NS for all). Exercise capacity was also significantly deteriorated in hypertensives with EBPR based on the lower values of achieved METs (9.95±2.3 vs 11±2.3, p=0.003). Peak systolic BP at exercise was correlated with 24-hour systolic BP (r=0.240, p&lt;0.001), 24-hour PP (r=0.218, p=0.001), PWV (r=0.152, p=0.046) and E/Em (r=0.150, p=0.049). Multiple logistic regression analysis revealed that PWV was the only independent predictor of EBPR (OR=1.31, p=0.047). Conclusions: EBPR constitutes a sign of cardiovascular stiffening in the setting of newly diagnosed EH, further elucidating the adverse prognostic role of abnormal systolic BP elevation at peak exercise.