tbuckley/cabot-search huggingface dataset:
Abstract 5020: Effect of Rivaroxaban on Markers of Coagulation in Patients With Acute Coronary Syndromes: An ATLAS ACS-TIMI 46 Substudy
Authors: C. Michael Gibson, Jessica L Mega, Lisa K Jennings, Satishkumar Mohanavelu, Frank Misselwitz, Alexei Plotnikov, Xiang Sun, Robert Zolynas, Eugene Braunwald
Journal: Circulation (2009)

Background: Prothrombin fragments 1 and 2 (F1.2) and D-dimer (DD) are sensitive circulating markers of thrombin generation and fibrinolysis, respectively. Elevated concentrations of F1.2 and DD in ACS patients have been associated with adverse outcomes. Methods: In ATLAS ACS-TIMI 46, patients were randomized to placebo or the factor Xa inhibitor rivaroxaban (5–20 mg) twice daily (BID) or the same total daily dose once daily (QD). Blood samples were obtained at baseline, 8–24 hrs, and 180 days after drug administration. Results: 1,006 subjects were included to date in this substudy. At baseline, F1.2 and DD levels were similar in the placebo, rivaroxaban BID, and rivaroxaban QD groups (F1.2: 241, 251, 259 pMol/L; DD: 0.69, 0.79, 0.76 μ g/ml). Compared with placebo, rivaroxaban was associated with a significant reduction in F1.2 levels 8–24 hrs after administration in both the BID (240 vs 209 pMol/L, P&lt;0.01) and QD (240 vs 177 pMol/L, P&lt;0.001) groups. DD at baseline vs 8 –24 hrs was significantly increased in placebo patients (0.69 vs 0.75 μ g/ml, P&lt;0.05), but unchanged in patients receiving rivaroxaban. By day 180, F1.2 and DD were reduced in placebo patients, presumably because the previous thrombotic state had dissipated; however, patients receiving rivaroxaban continued to have even lower concentrations of both markers of coagulation (Figure ). Conclusions: In patients with ACS, rivaroxaban is associated with a significant, early reduction in F1.2 that persists throughout 180 days of treatment, as well as a reduction in DD evident at 180 days. These findings may explain, in part, the mechanism by which rivaroxaban reduces major cardiovascular events in patients following an ACS.
Abstract 4915: IQGAP1 Expressed in Macrophage and Endothelial Cells Plays an Important Role in ROS-dependent Ischemia-induced Neovascularization
Authors: Norifumi Urao, Ronald D McKinney, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation (2009)

Not only endothelial cells (ECs) but also macrophage play a key role in ischemia-induced angiogenesis which is dependent on inflammation and reactive oxygen species (ROS). IQGAP1, an actin- and Rac1-binding scaffold protein, is a key regulator for actin cytoskeleton and motility. We demonstrated that IQGAP1 is involved in VEGF-induced ROS production and migration in cultured ECs; however, its role in post-ischemic neovascularization remains unknown. Using hindlimb ischemia model of mice, here we show that IQGAP1-expressing Mac3-positive macrophage and lectin-positive ECs (5.5 and 10.2-fold) are increased in ischemic limb tissues at 3 days and 7 days after ischemia, respectively. Ischemia-induced neovascularization is significantly impaired in IQGAP1 knockout (KO) mice as compared to wild-type (WT) mice as evaluated by laser Doppler blood flow (38% decrease), capillary density (48% decrease), and alpha-actin+ arterioles (68% decrease). In IQGAP1 KO mice, the number of infiltrated Mac3-positive macrophage and ROS production in ischemic muscles are significantly decreased (30% and 52%, respectively). In contrast, numbers of inflammatory cells and cKit+/Flk1+ endothelial progenitor cells (EPCs) in peripheral blood are not affected in these knockout mice. As compared to WT-BM transplantation to irradiated WT mice, WT-BM to irradiated KO mice inhibits ischemia-induced in blood flow recovery (22%) and CD31+ capillary density (5%), while KO-BM to irradiated WT mice shows decreases in flow recovery (48%) and capillary density (23%). These findings indicate that IQGAP1 KO mice impair function of BM derived cells without affecting their mobilization from BM. Furthermore, in vitro, BM-derived macrophages obtained from KO mice show defective polarization of actin (88% decrease), as visualized by phalloidin staining as well as inhibition of migration induced by SDF-1 (92%) or wound scratch (38%). VEGF- or wound scratch-induced EC migration is inhibited in IQGAP1-depleted ECs. In summary, IQGAP1 upregulated in macrophage and ECs after hindlimb ischemia plays an important role in ROS-dependent postnatal neovascularization. Thus, IQGAP1 is a potential therapeutic target for inflammation- and angiogenesis-dependent cardiovascular diseases. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota &amp; Wisconsin).
Abstract 5195: Forced Angiogenesis in Adventitia Promotes Plaque Formation in Abdominal Aorta of Apolipoprotein E-deficient Mice
Authors: Kimie Tanaka, Daisuke Nagata, Yasunobu Hirata, Yasuhiko Tabata, Ryozo Nagai, Masataka Sata
Journal: Circulation (2009)

Background: Accumulating evidence suggests that exaggerated formation of vasa vasorum plays an important role in the pathogenesis of atherosclerotic plaque progression. It was reported that enhanced angiogenesis in adventitia promoted lesion progression after mechanical vascular injuries. However, it remains unclear whether augmented angiogenesis in adventitia could promote hyperlipidemia-induced atherosclerotic lesion formation. Methods: We investigated whether local administration of slow-releasing form (30 days) of basic fibroblast growth factor (bFGF) promotes plaque progression with enhanced perivascular angiogenesis. bFGF (100 μ g/body) incorporated in acid gelatin hydrogel microspheres (AGHMs) (bFGF+AGHM group, n=4), AGHMs (AGHM group, n=7), or PBS (control group, n=9) was administrated into periaortic areas of retroperitoneal space of 10 to 11-week-old male ApoE-deficient mice. The mice were fed on western type diet. The abdominal aorta was harvested with perivascular soft tissues at 13 weeks after the operation. Staining with Lycopersicon Esculentum (Tomato) lectin was performed to visualize micro-vessels at 5 different sections from each aorta. Results : Larger lesions were observed only in the bFGF+AGHMs group ( bFGF+AGHM: 3.5×10 4 ±1.2 × 10 4 μ m 2 , AGHM:0.8 × 10 4 ±0.7×10 4 μ m 2 , control 0 μ m 2 , p&lt;0.005). Plaque formation was associated with increased neovascularization in the adventitia. When the aortic section were divided into 16 radial areas, there was a relation between the number of capillaries and the plaque size (r=0.77, p&lt;0.001). In time course study, proliferation of vasa vasorum and accumulation of Mac3-positive macrophages were observed prior to atherosclerotic lesion formation. Conclusions: Local administration of bFGF in adventita induces development of vasa vasorum, which potentially accelerates plaque lesion progression in ApoE-deficient mice.
Abstract 586: Hydroxycholesterol or Cyclic AMP Upregulates the Expression of Renin in Human Mesenchymal Stem Cells
Authors: Kenichi Matsushita, Fulvio Morello, Richard E Pratt, Victor J Dzau
Journal: Circulation (2006)

Renin is a key enzyme in the renin-angiotensin system which plays a vital role in the regulation of cardiovascular homeostasis. Metanephric mesenchymal cells are assumed to be the origin of vascular smooth muscle cells and of renin precursor cells. It is also suggested that renin precursor cells are metaplastically modified smooth muscle cells and/or precursor of smooth muscle cells during ontogeny. However, there is no direct evidence that mesenchymal stem cells (MSCs) can be induced to become renin expressing cells. Previously we have reported that the nuclear hormone receptor liver X receptor (LXR) is a major transcriptional regulator of renin gene expression. In this study we examined the effect of LXR agonists on renin gene expression in human mesenchymal stem cells. Methods: Human mesencymal stem cells were subjected to serum starvation for 16 hours. We then added the LXR natural ligand 22-hydroxycholesterol (10 -7 M) and investigated mRNA expression of renin and ATP-binding cassette transporter A1 (ABCA1) which is well known upregulated by LXR activation after 6 hours of pharmacological treatment by using real-time RT-PCR. We further examined the renin and ABCA1 mRNA expression by adding cyclic AMP (10 -3 M). Results: Human MSCs treated with 22-hydroxycholesterol exhibited an increase in expression of renin (1.7 ± 0.3 fold change for MSCs without treatment, P &lt; 0.05). There was an increase in ABCA1 expression (1.6 ± 0.1 fold change, P &lt; 0.05), suggesting that 22-hydroxycholesterol effectively acted as a LXR ligand. Furthermore, cyclic AMP showed also upregulated renin and ABCA1 mRNA expression (2.2 ± 0.3 and 1.9 ± 0.1 fold changes for MSCs without treatment, respectively, P &lt; 0.05). Conclusion: Our results suggest that the activation of liver X receptor upregulates renin mRNA expression in human mesenchymal stem cells and suggest that these cells may be the origin of renin cells during embryonic development. Our observations provide insight into possible novel understanding of the renin-angiotensin system (RAS) and RAS related cardiovascular disease.
Abstract 5136: Reduction in Myocardial Ischemia-reperfusion Injury in Group IV Cytosolic Phospholipase A <sub>2</sub> -deficient Mice Partly Due to Inhibition of TNF <i>α</i> -mediated Pathway to Cell Injury
Authors: Yukio Saito, Yousuke Watanabe, Hideto Mishina, Kazuhiro Watanabe, Toshiaki Yano, Tsuyoshi Kobayashi, Jun-ei Obata, Ken-ichi Kawabata, Takao Shimizu, Kiyotaka Kugiyama
Journal: Circulation (2009)

Type IV cytosolic phospholipase A 2 (cPLA 2 ), which preferentially cleaves arachidonic acid from phospholipids, plays an important role in tissue injury. The downstream signal in response to TNF α , a key mediator of myocardial ischemia reperfusion (I/R) injury, involves cPLA 2 activation. This study examined a pathogenic role of cPLA 2 and its mechanistic link with TNF α in myocardial I/R injury using cPLA 2 α knockout mice (cPLA 2 −/− mice). Methods and Results: The cPLA 2 −/− mice with C57BL/6 background used in this study had comparable heart size, heart rate and blood pressure with the littermate cPLA 2 +/+ (wild-type; WT) mice (male at 10 weeks). In vivo myocardial I/R was created in 10-week-old male mice by 1-hr ligation of the left anterior descending coronary artery, followed by 24 hrs of reperfusion. Expression levels of mRNA and protein of TNF α in the ischemic myocardium were increased from baseline by 5-fold similarly in both cPLA 2 −/− and WT mice. Expression of TNF α receptors was unchanged after I/R in both genotypes. cPLA 2 −/− mice had a 45% reduction in myocardial infarct size and a preservation of LV fractional shortening (25% vs. 15%, respectively) after I/R compared with WT mice. The contents of thromboxane B 2 and leukotriene B 4 , arachidonic acid-derived proinflammatory mediators, in injured myocardium were 40% ~ 50% lower in cPLA 2 −/− mice than WT mice. cPLA 2 −/− mice had a 30% decrease in caspase-3 activity and a 40% decrease in TUNEL-positive apoptotic cells in injured myocardium compared with WT mice. In cultured cardiomyocytes from WT mice, hypoxia-reoxygenation (H/R) induced cPLA 2 activation that was suppressed by preincubation with the TNF α -neutralizing antibody. Incubation of cardiomyocytes with TNF α induced apoptosis, cell damage (MTT assay) and production of thromboxane B 2 and leukotriene B 4 that were attenuated in cPLA 2 −/− cardiomyocytes compared with WT cardiomyocytes. H/R exhibited similar results obtained from TNF α . Preincubation with the TNF α antibody significantly inhibited H/R-induced apoptosis and cell damage in WT cardiomyocytes, while it did not in cPLA 2 −/− cardiomyocytes. Conclusions: Disruption of cPLA 2 attenuated myocardial I/R injury partly through inhibition of TNF α -mediated pathway to cell injury and apoptosis.
Abstract 5208: S-glutathiolation Uncouples Endothelial Nitric Oxide Synthase: A Novel Mechanism of Redox Signaling and Vascular Regulation
Authors: Chun-An Chen, Tse-Yao Wang, Saradhadevi Varadharaj, Levy Reyes, M.A. Hassan Talukder, Yeong-Renn Chen, Lawrence J Druhan, Jay L Zweier
Journal: Circulation (2009)

Superoxide (·O 2 − ) and secondary oxidants are critical mediators of cellular signaling, proliferation and apoptosis. In response to oxidative stress, protein thiols undergo S-glutathiolation forming mixed disulfides and this modification plays an important role as an adaptive response to oxidative injury in cells, controlling cellular signaling in a manner similar to protein phosphorylation. We investigated the effects of S-glutathiolation on the regulation of eNOS function in vitro . We observe that S-glutathiolation greatly reduces NO synthase activity (70% ± 1%), and this loss of activity was reversed by DTT. In contrast, only a 56%±0.9% decrease in NADPH consumption was seen that was only partially inhibited by L-NAME or the calcium chelator EGTA, implicating an increase in eNOS derived ·O 2 − . Using EPR spin-trapping to directly measure eNOS derived ·O 2 − , we proved that S-glutathiolation greatly increased ·O 2 − generation from the enzyme. S-glutathiolation of human eNOS increased ·O 2 − generation &gt;5-fold and L-NAME and EGTA only partially blocked this ·O 2 − generation. Thus, S-glutathiolation uncouples eNOS greatly increasing ·O 2 − generation and the partial or complete lack of inhibition of this by L-NAME and EGTA indicates that the observed ·O 2 − is largely derived from the reductase domain. Mass spectrometric analysis and molecular modeling revealed that two sights of S-glutathiolation in eNOS are two highly conserved cysteines found at the interface between the FMN and FAD-binding domains, C 689 and C 908 . The modification of these two cysteins appears to interrupt electron transfer to the oxygenase domain, leading to electron leakage. Furthermore, we observe that BCNU and H 2 O 2 - derived oxidative stress induces S-glutathiolation of eNOS in endothelial cells, with measured loss of NO and gain of ·O 2 − generation, and we show that this process impairs endothelium-dependent vasodilation. Additionally, we observe that in hypertensive vessels eNOS-S-glutathiolation is increased with impaired endothelium-dependent vasodilation that is restored by thiol-specific reducing agents. Thus, S-glutathiolation of eNOS serves as a pivotal switch that provides redox regulation of endothelial function and vascular tone. This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania &amp; West Virginia).
Abstract 4755: Serial Changes in Coronary Vessel Remodeling During Plaque Progression Are Related to Alterations in Plaque Composition as Seen on Integrated Backscatter Intravascular Ultrasound
Authors: Shinji Inaba, Hideki Okayama, Jun-ichi Funada, Hidetoshi Hashida, Go Hiasa, Takumi Sumimoto, Yasunori Takata, Katsuji Inoue, Akiyoshi Ogimoto, Tomoaki Ohtsuka, Jitsuo Higaki
Journal: Circulation (2009)

Background: Studies have demonstrated that coronary arteries with initial atherosclerosis show outward (positive) remodeling in order to maintain luminal diameter. However, serial changes in coronary vessel remodeling and its relation to alterations in plaque composition have not been investigated. Recently, assessment of plaque composition has become possible using an integrated backscatter intravascular ultrasound system (IB-IVUS). Using IB-IVUS, we examined whether the progression of coronary vessel remodeling is associated with changes in plaque components. Methods: One hundred sixty non-culprit, intermediate lesions were identified in 88 patients. Seventy-eight plaques demonstrated plaque progression at follow up examination and were included in this study. Plaque progression was defined as a &gt;5% increase in plaque volume. A total of 20 IB-IVUS images were recorded at 0.5 mm intervals along a 10 mm length of plaque. Total vessel volume (TVV) on conventional IVUS, total lipid volume (TLV) and total fibrous volume (TFV) on IB-IVUS were measured at each site. Six months later, a follow up IVUS examination was performed of the same coronary segment imaged at baseline. Serial changes in vessel remodeling (vessel remodeling index: VRI) were calculated as TVV at follow up examination/TVV at baseline examination. Progressive plaques were divided into two groups (compensation: 52 plaques, C-group VRI&gt;1; no compensation or shrinkage: 26 plaques, S-group VRI≤1). Results: TLV and TFV at baseline examination were not significantly different between the two groups. However, ΔTLV (TLV at follow up examination - TLV at baseline examination) in the C-group was significantly higher compared to the S-group (10.0±8.6 vs. 2.7±7.0 mm 3 , P&lt;0.01). Conversely, ΔTFV (TFV at follow up examination - TFV at baseline examination) in the C-group was significantly lower compared to the S-group (2.9±5.6 vs. 6.5±3.9 mm 3 , P&lt;0.01). The VRI positively correlated with ΔTLV (r=0.34, P&lt;0.01), but not with ΔTFV. Conclusions: Serial changes in coronary vessel remodeling are associated with alterations in the lipid component of progressively enlarging plaques.
Abstract 5203: Arterial Stiffness and Urinary Albumin Excretion in Hypertension: The Emerging Role of the Soluble Receptor for Advanced Glycation End Products
Authors: Kyriakos Dimitriadis, Costas Tsioufis, Costas Thomopoulos, Ioannis Andrikou, Hraklis Tatsis, Nikolaos Kalovidouris, Vanessa Tzamou, Eleftherios Tsiamis, Christodoulos Stefanadis
Journal: Circulation (2009)

Introduction: Current evidence suggests that the soluble receptor for advanced glycation end products (sRAGE) participates in the development of vascular disease, while albuminuria and arterial stiffening are associated with atherosclerosis progression. Hypothesis: Urinary albumin excretion, expressed as the albumin to creatinine ratio (ACR), may be related to sRAGE and arterial stiffness in essential hypertensives. Methods: Our population consisted of 80 newly diagnosed untreated non-diabetic patients with stage I to II essential hypertension [48 men, mean age=52 years, office blood pressure (BP)=145/93 mmHg]. According to the ACR values determined as the mean of two non-consecutive morning spot urine samples, patients were divided into microalbuminurics (n=27) (mean ACR=30 –300 mg/g) and normoalbuminurics (n=53) (mean ACR&lt;30 mg/g). Moreover, arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV), by means of a computerized method (Complior SP). Results: Microalbuminurics compared to normoalbuminurics were older (53±6 vs 49±5 years, p&lt;0.05), had higher 24-h systolic BP (140±13 vs 132±12 mmHg, p=0.001), while did not differ regarding sex and metabolic profile (p=NS). Moreover, microalbuminurics compared to normoalbuminurics exhibited higher levels of PWV (8.9±1.8 vs 7.9±1.5 m/sec, p&lt;0.0001), whereas had lower sRAGE (1011±458 vs 1503±931 pg/ml, p=0.003), independently of confounders. In the total population, ACR was positively related to 24-h systolic BP (r=0.514, p&lt;0.0001) and PWV (r=0.588, p&lt;0.0001), whereas it was negatively correlated with sRAGE (r=−0.275, p=0.018). Regarding sRAGE, it was associated with body mass index (r=−0.241, p=0.003), 24-h pulse pressure (r=−0.372, p=0.001) and PWV (r=−0.403, p&lt;0.0001). Multiple regression analysis revealed that age, 24-h systolic BP, PWV and sRAGE were the independent predictors of ACR ( R 2 =0.49, p&lt;0.0001). Conclusions: In hypertension, microalbuminuria is accompanied by pronounced arterial stiffening and diffuse vascular dysfunction as reflected by lower sRAGE levels. Moreover, the association of sRAGE with ACR and PWV, underscores the catalytic role of this receptor in the progression of the hypertensive atherosclerotic disease.
Abstract 5450: Detection of Intracoronary Thrombus by Magnetic Resonance Imaging in Patients With Acute Coronary Syndrome
Authors: Christian H Jansen, Divaka Perera, Andrea J Wiethoff, Marcus R Makowski, Timothy Lockie, Andreas Indermuehle, Reza M Razavi, Amedeo Chiribri, Eike Nagel, Gerald F Greil, Simon Redwood, Rene M Botnar
Journal: Circulation (2009)

Background: Persistent intracoronary thrombus following plaque rupture is associated with an increased risk of subsequent myocardial infarction and mortality. Presently, coronary thrombus can only be visualized invasively by X-Ray Angiography (XRA), intravascular ultrasound, or angioscopy. Purpose: The aim of this study was to investigate the use of non-contrast enhanced magnetic resonance imaging for direct thrombus visualization (MRDTI) in patients with a recent ACS (troponin T &gt;1.0). Method and Results: 14 patients (13 male) underwent MRDTI within 24 –72h of presenting with ACS prior to invasive X-ray angiography (XRA). MRDTI (fig. a ) was performed using a navigator-gated free breathing and cardiac-triggered T1-weighted 3D inversion-recovery black-blood gradient-echo sequence without contrast administration. 7 patients were found to have intracoronary thrombus on XRA ±/− thrombus extraction (2xLAD, 1xLCX, 3xRCA and 1PDA branch of RCA) (fig c .) and 7 had no visible thrombus. MRDTI (fused with magnetic resonance angiography, fig. b ) correctly identified thrombus in 6 of 7 patients (PDA thrombus not detected) and correctly classified the control group of 7 patients without thrombus formation. Contrast to noise ratio of thrombus as compared to the vessel lumen of non-affected segments was 6-fold increased (67.5±12.2 vs. 10.2±6.6, p &lt;0.01). Conclusion: MRDTI allows selective visualization of coronary thrombus in patients after myocardial infarction. This technique may be useful for direct coronary thrombus detection in patients with ACS or unstable angina.
Abstract 4173: Statin Use is Associated with Higher Levels of Total and Long-Chain n-3 Fatty Acids and Lower Levels of n-6 and Saturated Fatty Acids in Patients Following Acute Myocardial Infarction
Authors: Anil Nigam, Nancy Frasure-Smith, Francois Lespérance, Pierre Julien
Journal: Circulation (2006)

Background: Higher plasma n-3 fatty acid levels are associated with improved long-term outcomes in the primary and secondary prevention of CHD. Besides anti-arrhythmic effects, n-3 fatty acids have been shown to possess other pleiotropic effects including anti-inflammatory and antithrombotic effects in a fashion similar to statins. The effect of statin use on fatty acid synthesis and metabolism has received little attention in CHD patients. The objective of this study was to evaluate the relationship between statin use, plasma fatty acid levels and estimated desaturase activity in patients following acute myocardial infarction. Methods: Clinical and metabolic parameters including fasting plasma fatty acid levels were measured in 734 subjects, approximately eight weeks following AMI. Correlations were evaluated between statin use, fatty acid levels and desaturase activity. Results: Statin use was observed in 539 of 734 patients and was associated with higher levels of total n-3 (r=0.10, P=0.005) and long-chain n-3 fatty acids (ecosapentanoeic acid r=0.11, P=0.004; docosahexanoeic acid r=0.12, P=0.001) and lower n-6 (linoleic acid r=-0.24, P&lt;0.001) and total saturated fatty acid levels (r=-.083, P=0.025). Multivariate models adjusted for age, sex, smoking, physical activity level and the components of the metabolic syndrome did not significantly alter the observed associations. Statin use correlated negatively with estimated Δ-9 desaturase activity (r=-0.08, P=0.025) and positively with Δ-5 activity (r=0.23, P&lt;0.001). Conclusions: Statin use is associated with an improved plasma fatty acid profile characterized by higher levels of total and long-chain n-3 fatty acids and lower levels of saturated and certain n-6 fatty acids. We cannot exclude that dietary factors may have influenced the observed associations. Our data is consistent with basic science investigations and randomized trials in non-CHD patients demonstrating that statins do influence fatty acid synthesis and metabolism. Whether the pleiotropic effects of statins may in part be due to an improved fatty acid profile requires further study in prospective clinical trials.