tbuckley/cabot-search huggingface dataset:
Abstract 4957: Robust Transfection of Vascular Endothelium for siRNA Knockdown of Vascular Cell Adhesion Molecule-1 Through a Novel Nanoparticle-Lipid Raft Pathway
Authors: Megan M Kaneda, Gregory M Lanza, Samuel A Wickline
Journal: Circulation (2009)

Controlling adhesion molecule expression as an antiatherosclerotic therapy is a heretofore untested concept that could modify disease progression and/or interdict acute coronary syndromes. Methods: To design a synthetic vehicle to deliver vascular cell adhesion molecule-1 (VCAM-1) siRNA to endothelial cells, perfluorocarbon nanoparticles (PFC-NP) were loaded with the cationic lipid 1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP) in the lipid monolayer to form transfection complexes (10 pM PFC-NP + 5 nM siRNA) with VCAM-1 specific siRNA. Mouse 2F2B endothelial cells were treated with TNF α (10 ng/ml) to induce VCAM-1 expression and after 48h, mRNA and protein levels were measured. For endocytosis colabeling studies, transfection complexes were produced with fluorescently labled siRNA (red) and incubated with endothelial cells in the presence of fluorescently labeled pathway specific markers (green, macropinocytosis: dextran, clathrin: transferrin, lipid raft: cholera toxin-B). Results: PFC-NP mediated siRNA transfection led to a significant decrease in both VCAM-1 mRNA and protein levels(A) . siRNA exhibited little intracellular colocalization with common markers of both macropinocytosis (B) and clathrin mediated endocytosis (C), while abundant membrane colocalization with lipid rafts was observed(D). Conclusion: Because endothelial cells harbor an excess of lipid rafts in their plasma membranes, the development of an effective targeted nanoparticle carrier for siRNA that utilizes lipid raft transport rather than traditional endocytotic pathways could represent a valuable strategy for controlling vascular inflammation in atherosclerosis. 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 4949: Bleeding and Ischemic Complications in Patients With Acute Coronary Syndromes and Chronic Kidney Disease in Relation to Different Glycoprotein IIb/IIIa Inhibitors: Analysis From the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) Trial
Authors: Olayinka Afolabi-Brown, Eugenia Nikolsky, Alexandra J Lansky, Roxana Mehran, Martin Fahy, Brent T McLaurin, David A Cox, Frederick Feit, Antonio Colombo, Adriano Caixeta, Gregg W Stone
Journal: Circulation (2009)

Objectives: We evaluated outcomes of moderate- to high-risk patients (pts) with acute coronary syndromes (ACS) and chronic kidney disease (CKD) receiving alternative antithrombotic therapy in the ACUITY trial. Background : Knowledge of safety and efficacy of different antithrombotic medications is important considering the choice of therapy in pts with ACS having CKD. Methods: In the ACUITY trial, 2468(19.1%) pts had CKD (baseline creatinine clearance &lt;60 ml/min) and 10,472 (80.9%) pts had preserved renal function. Pts were randomized to receive 1 of 3 antithrombotic regimens including heparin + glycoprotein IIb/IIIa inhibitors (H + GPI), bivalirudin (Biv) plus a GPI, or Biv alone. Type of GPI (abciximab or a small-molecule GPI [eptifibatide and tirofiban]) was at operator’s discretion. Dosages were adjusted for renal function. Patients treated with Biv + a GPI were excluded from this analysis. Results : 30-day outcomes are presented in the table . Regardless of antithrombotic regimen, CKD was associated with remarkable increase in ischemic events, and more than 2-fold increase in rates of major bleeding. In pts with CKD, there were no significant differences in rates of major bleeding among those who received H +a small-molecule GPIs vs abciximab (p=0.7). In pts with CKD, Biv monotherapy compared to H +a small-molecule GPIs resulted in remarkably lower rates of major bleeding (p=0.003) without increase in rates of ischemic events. Bivalirudin monotherapy resulted in non significantly lower rates of bleeding than H+abciximab (p=0.3). Conclusions: CKD is associated with higher rates of 30-day ischemic events and major bleeding. Rates of major bleeding did not differ significantly between small-molecule GPIs and abciximab when used in conjunction with heparin in pts with ACS and baseline CKD. In pts with or without CKD, bivalirudin monotherapy resulted in the lowest rates of hemorrhagic events without increasing risk of ischemic complications.
Abstract 609: Erythropoietin-Mediated Protection Against Hypoxia/Reoxygenation Injury in Human Muscle is via Phosphatidylinositol-3-Kinase and P42/44 Kinase Activation
Authors: Naveen R Mudalagiri, Derek M Yellon
Journal: Circulation (2006)

The renal cytokine Erythropoietin (EPO) has in animal studies demonstrated myocardial protection, this being linked to the activation of pro-survival signalling cascades, phosphatidylinositol-3-kinase (PI3K) and p42/44 extra-cellular signal-regulated kinases. This protection and the mechanisms associated with it have to date not been observed in human myocardium. We investigated the ability of EPO to protect human atrial trabeculae obtained from patients undergoing coronary artery bypass surgery. Since PI3K has been shown to be down regulated in diabetic animal studies we also examined the ability of EPO to protect human muscle from type 2 diabetic patients. Isolated human atrial trabeculae were suspended in an organ bath and exposed to 90 minutes of hypoxia followed by 120 minutes of reoxygenation. EPO (50ng/ml) was administered throughout reoxygenation following simulated ischemia. Cardiac function was assessed by measuring the developed force of contraction which was calculated as a percentage of baseline force of contraction. EPO improved force of contraction when administered at reoxygenation (46.7% +/− 1.7 vs. 30.2% +/− 2.2 for control, p&lt; 0.001). These effects were abrogated by the PI3K inhibitor, LY294002 (29.4% +/− 2.5 vs. 30.2% +/−2.2 for control) and P42/44 inhibitor, UO126 (31.5% +/− 2.5 vs. 30.2% +/− 2.2 for control). EPO and preconditioning (as a positive control) offered similar degrees of protection (46.7% +/− 1.8 vs. 51.2% +/− 1.4 for preconditioning). In the diabetic group, EPO improved force of contraction (38.3% +/− 1.4 vs. 30.2% +/− 2.2 for control, p&lt;0.05). However, the degree of cardioprotection was less than that observed in the non diabetic group (38.3% +/− 1.4 vs. 46.7% +/− 1.7 for non diabetic EPO group, p&lt;0.005). EPO administered at reoxygenation protects the human muscle via the PI3K and P42/44 dependent pathways. Inhibiton of either pro-survival kinase results in loss of cardiac protection. EPO cardioprotection was also observed in the diabetic group, although still significant, was not of the same magnitude as observed in the non diabetic group. This data supports the potential use of EPO as a novel cardioprotective strategy when used alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.
Abstract 5170: Atrial Endothelial Impairment Induced by Toll-Like Receptor-4 Signaling May Cause Atrial Thrombogenesis
Authors: Shigehiko Katoh, Tetsu Watanabe, Satoshi Suzuki, Hiroki Takahashi, Takanori Arimoto, Tetsuro Shishido, Takehiko Miyashita, Takuya Miyamoto, Joji Nitobe, Isao Kubota
Journal: Circulation (2009)

Background Recently atrial endothelial dysfunction has gained more attention as an important cause for atrial thrombogenesis in patients with atrial fibrillation (AF). It was reported that AF patients with left ventricular hypertrophy or heart failure (HF) have higher thromboembolic risks than those without. Several reports showed that angiotensin II receptor blockers prevented occurrences of AF and thrombogenesis by inhibiting inflammation. However, little is known how AF causes atrial inflammation and thrombogenesis. We examined whether atrial inflammation through toll-like receptor (TLR)-4 signaling causes atrial thrombogenesis. Methods and result First, we examined serum and atrial tissue heat shock protein 60 (HSP60) levels, which have been known as a TLR-4 ligand, in patients with and without AF. Atrial HSP60 increased in HF patients with AF compared to those without AF whereas serum HSP60 level was lower in HF patients with AF compared to those without AF (NYHA class I and II). Then, we created thoracic transverse aortic constriction (TAC) model in TLR-4 knockout (KO) mice (n=15) and wild-type (WT) mice (n=20). We performed echocardiography at 4 weeks after TAC surgery. Then, the atrium was excised, and vascular cell adhesion molecule (VCAM)-1, endothelial nitric oxide synthase (eNOS), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and mitogen activated protein kinase p38 (p38) were analyzed by Western blotting. We observed less frequent occurrence of atrial thrombosis in TLR-4 KO-TAC mice (4/15) than WT-TAC mice (16/20). Decrease in eNOS phosphorylation and increase in VCAM-1 expression in WT-TAC mice were significantly attenuated in TLR-4 KO-TAC mice (P&lt;0.05). Nuclear factor-kappa B (NFkB) was attenuated in TLR-4 KO-TAC mice compared to WT-TAC mice by electrophoretic mobility shift assay analysis. Phosphorylation of p38, but ERK and JNK was also attenuated in TLR-4 KO-TAC mice (P&lt;0.05). These results suggested that activation of VCAM-1 and decreased eNOS through TLR-4/p38 and NFkB signaling may be associated with atrial thrombogenesis in AF. Conclusion Atrial inflammation caused by TLR-4 signaling may play a role in atrial thrombogenesis in heart failure mice model.
Abstract 5101: ACS in Patients With and Without Spontaneous Dissections of Coronary Arteries: The Discovery Study
Authors: Leopoldo Pagliani, Luigi La Vecchi, Ester Cabianca, Carlo Bonanno, Alessandra Benettin, Alessandro Desideri, Alessandro Santarelli, Andrea Manari, Alberto Benassi, Alessandro Fontanelli
Journal: Circulation (2009)

Spontaneous coronary dissection ( SCAD) is an unusual, life threatening cause of acute myocardial ischemia. Over 200 cases of SCAD have been reported in the literature but, most of the available clinical information about SCAD derives from case reports and prospective data are lacking. The purpose of DISCOVERY study (DISsection of COronary Arteries: Veneto and Emilia RegistrY) was to prospectively assess clinical characteristics, treatment and outcome of SCAD pts. w/o spontaneous dissections with comparable pts. and to attempt to assess the role of SCAD in the pathogenesis of Acute Coronary Syndromes (ACS) and to determine whether peculiar clinical characteristics may help in defining a diagnostic pattern for SCAD-ACS. From October ’05 to December ’07, 42 consecutive pts ( mean age 51 yrs) were enrolled in the Cardiology Units of the Veneto and Emilia regions. Only cases of angiographically-proven SCAD of major coronary branches were included. Concomitantly, the first incoming ACS pts following a SCAD pts of comparable age and sex was enrolled. Insodoing, a control group of non-SCAD ACS was obtained. Analysis report data on two groups (ACS and SCAD-ACS) in order to analyze presentation, treatment strategies and outcome. In the SCAD-ACS group, no case was associated with peripartum, nor any showed associated carotid disease or lens subluxation. Baseline characteristics were similar in SCAD and non-SCAD ACS. However, SCAD pts had fewer risk factors (r.f.) for coronary disease (p=0.0016), The LAD coronary artery was more commonly involved. Also, presenting ecg pattern was more frequently ST elevation in SCAD compared to non-SCAD (58% vs 33%). Treatment were significantly different in the 2 groups: 54 % of SCAD population had conservative treatment vs 31% in the control group (p=0.002). In revascularized pts, PCI was by far the preferred treatment option. All pts were discharged alive in both groups. During a 18 month f.u., incidence of MACE was 2.3% in SCAD vs 27% in non-SCAD (p&lt;0.001). Our data show how SCAD-ACS pts have fewer coronary r.f. compared to non-SCAD-ACS of comparable age, are less prone to undergo revascularization and exibit a much better long-term prognosis. Some features of SCAD-ACS traditionally considered in SCAD do not appear to be such in our series.
Abstract 5112: Contribution of Th17 Cells, a New Subset of CD4 <sup>+</sup> T Cells, to Angiogenic Response to Hindlimb Ischemia
Authors: Takeki Hata, Masafumi Takahashi, Masanori Kawaguchi, Yu-ichiro Kashima, Atsushi Izawa, Shigeaki Hida, Yo-ichiro Iwakura, Shinsuke Taki, U-ichi Ikeda
Journal: Circulation (2009)

Background: Accumulating evidence suggests contribution of T cell to the collateral development in ischemic tissue; however, its mechanism remains unclear. Th17 cells are recently identified as a new subset of CD4 + T cells and specifically secrete interleukin-17 (IL-17). Here, we investigated the role of CD4 + T and Th17 cells in the induction of angiogenesis. Methods and Results: Unilateral hindlimb ischemia was produced in wild-type mice (WT, C57BL/6). Neutralization using anti-CD4 antibody resulted in complete depletion of CD4 + T cells (flow cytometry) and a significant reduction of blood flow perfusion (laser Doppler perfusion imaging, LDPI: 0.61±0.08 vs. 0.41±0.11 p&lt;0.05) in the ischemic limbs. Since IL-6, inducer of Th17 cells, was upregulated in the ischemic limbs, we next focused on Th17 cells. The expression of IL-17 and RORgt (Th17 regulator) was upregurated in the ischemic limbs, but not in the contralateral limbs. IL-17-deficient (IL-17 −/− ) mice also showed a significant decrease in angiogenesis, compared with WT mice (LDPI: 0.72±0.26 vs. 0.38±0.27, p&lt;0.01), accompanied with significant reduction of capillary formation (CD31 immunostaining: 1223.3±267.3/mm 2 vs. 692.9±165.6/mm 2 , p&lt;0.01). Immunostaining and flow cytometry showed decreased infiltration of neutrophils, monocyte/macrophages, and CD4 + T cells in the ischemic limbs of IL-17 −/− mice (p&lt;0.05). The levels of angiogenic factors such as IL-1b and VEGF-A were also decreased in the ischemic limbs of IL-17 −/− mice (p&lt;0.05). To determine the contribution of bone marrow-derived Th17 cells, bone marrow-transplanted mice (BMT) were prepared. BMT IL-17−/− to Wild showed a significant decrease in angiogenic response, compared with BMT Wild to Wild (LDPI: 0.60±0.15 vs. 0.24±0.11, p&lt;0.05). To assess the effect of Th17 cells on angiogenesis, spleen-derived CD4 + T cells from IL-17 −/− or WT mice were implanted into the ischemic limbs of athymic mice. Implantation of CD4 + T cells from IL-17 −/− mice showed a significant reduction of angiogenic response, compared with those from WT mice (LDPI: 0.71±0.17 vs. 0.51±0.13, p&lt;0.05). Conclusion: CD4 + Th17 cells contribute to the angiogenic response and provide new insights into the mechanism by which T cells promote collateral development.
2006 James B. Herrick Award and Lecture—Drug-Eluting Stents: The Beginning of the End or the End of the Beginning?
Authors: Patrick Serruys
Journal: Circulation (2006)

In 2003–2004, drug-eluting stents (DES) were approved by regulatory bodies in the European Union and United States. Pivotal studies in the preceding year had demonstrated a major treatment effect (60% to 80%) on angiographic restenosis irrespective of the type of lesion or clinical syndrome. Interventional cardiologists worldwide swiftly embraced this new modality of treatment, with market penetration of 30% to 90%. This disruptive technology—without evidence base— has already had a major impact on our approach to coronary revascularization. Patients traditionally referred for surgery are now revascularized percutaneously. But in 2008–2009, results of major trials comparing percutaneous coronary intervention with coronary artery bypass grafting (SYNTAX, FREEDOM, COMBAT, CARDIA) in patients with 3VD and/or LMS may confirm the value of DES in “surgical” patients, and the beginning of the end of a surgical era might be on the horizon. On the other hand, worrisome information about late stent thrombosis is currently emerging. The drugs used are potent cytostatic or cytotoxic agents with long-term detrimental effects on endothelialization. Large investigator-driven registries with long follow-up suggest an unabated rate of late stent thrombosis even after 3 years. New pharmacological strategies (nonpolymeric reservoir, dual-drug elution, use of antithrombotic and antiinflammatory agents) and new absorbable metallic or nonmetallic platforms are currently being tested. The primary goal is no longer “oncologic” inhibition of neointimal hyperplasia but the restitution of a healthy and functionally active endothelial lining (eg, by capturing progenitor endothelial cells), capable—in conjunction with prohealing drugs (eg, NO donors)—of modulating the healing process without the use of permanent metallic stents. From this viewpoint, we are just at the end of the pioneering phase of the first generation of DES…and the end of the beginning.
A 22-Year-Old Female With Non-Hypertrophic Hypertrophic Cardiomyopathy
Authors: Rahul Sakhuja
Journal: Circulation (2009)

Abstract #3080 Rahul Sakhuja, Massachusetts General Hosp, Boston, MA; J. Eduardo Rame, Colleen Brown, Univ of California, San Francisco, San Francisco, CA; Karen Ordovas, Univ of Californa, San Francisco, San Francisco, CA; Philip Ursell, Univ of California, San Francisco, San Francisco, CA; Teresa De Marco, Univ of San Francisco, California, San Francisco, CA Rahul Sakhuja, 2009 Finalist and Presenting Author
2006 Charles T. Dotter Memorial Lecture—Cardiac Surgery: Pre- &amp; Post-Operative Insights From MR &amp; CT
Authors: Richard White
Journal: Circulation (2006)

Advancements in MR and CT imaging of the cardiovascular system have permitted unique insights into the appearance and behavior of the cardiac chambers, myocardium, coronary arteries, pericardium, and proximal great vessels in disease states directly involving or indirectly affecting (eg, such as due to valve disease) these structures. However, the impact of the 3D anatomic, functional, tissue-characterizing, or flow-quantification capabilities of these two noninvasive tomographic imaging modalities specifically on pre–cardiac surgery planning and/or post–cardiac surgery monitoring has not often been addressed. With concurrent advances in catheter-based therapy, there has been significant reduction in the volume of traditional cardiac surgical procedures such as coronary artery bypass grafting. Because of the life-saving nature of these surgical alternatives, traditional surgeries, and medical therapies, older patients with complicated medical histories, including prior interventions, leading to highly patient-specific cardiac conditions, are more and more commonly cardiac surgery candidates. Thus, there is increasing need for highly specialized and individualized imaging in order for cardiac surgeons to understand the specific details of such patients’ current cardiac anatomic and physiological abnormalities in the context of their past disease course and history of therapy to plan future surgical treatments. Cardiac surgical procedures performed at major heart centers that benefit from insights provided by cardiac MR and CT include ventricular restoration of the dilated dysfunctional left ventricle, myocardial revascularization of the chronically ischemic left ventricle, septal myectomy for hypertrophic obstructive cardiomyopathy, pericardiectomy for constrictive or adhesive pericardial disease, cardiac mass resection, and aortic root and/or valve replacement.
Abstract 4846: Rab5a-mediated Localization at Cell-cell Contacts of a Tight Junction Protein Claudin-1 is Regulated by Proteasome in Endothelial Cells
Authors: Machiko Asaka, Tetsuaki Hirase, Aiko Hashimoto-Komatsu, Koichi Node
Journal: Circulation (2009)

Increased endothelial permeability induced by inflammatory stimuli promotes atherosclerosis. Tight junction that is composed of transmembrane proteins, including claudin, and peripheral membrane proteins is a major barrier of endothelial permeability, whereas roles of claudin in the regulation of endothelial TJ permeability are not yet clear. We demonstrate that claudin-1 is dominantly expressed in cultured human endothelial cells by immonofluorescence and immunoblotting. To elucidate the physiological roles of claudin-1 in endothelial permeability, we depleted claudin-1 by RNA interference in endothelial cells. Depletion of claudin-1 protein expression significantly increased TJ permeability measured by transendothelial electrical resistance compared to control cells, indicating that claudin-1 is a crucial regulator of TJ permeability in endothelial cells. Ubiquitin-proteasome system has been implicated in the regulation of degradation and intracellular localization of proteins. We show that ubiquitin-proteasome system regulates claudin-1 localization from plasma membrane to cytoplasm using a proteasome inhibitor N-acetyl-Leu-Leu-Nle-CHO (ALLN) in endothelial cells. On the other hand, members of the small GTPase Rab protein family play important roles in intracellular vesicle transport and localization of membrane proteins. We examined colocalization of claudin-1 and Rab5a by confocal microscopy and studied the involvement of proteasome in the localization and the Rab-mediated transport of claudin-1 in endothelial cells. In control cells, claudin-1 was localized at cell-cell contact sites. In contrast, caludin-1 localization was observed at perinuclear regions in cytoplasm in association with Rab5a and EEA-1, a marker of early endosome, in ALLN-treated cells. Depletion of Rab5a by RNA interference reversed the localization of claudin-1 in ALLN-treated cells. These data suggest that Rab5a in early endosome is implicated in proteasome-mediated localization at cell-cell contacts of claudin-1 in endothelial cells. Rab5a-mediated intracellular transport of claudin-1 that is regulated by proteasome may play a role in the regulation of tight junction permeability in endothelial cells.
Abstract 5044: Aldose Reductase-Dependent Effects on Endothelial Dysfunction and Endothelial Progenitor Cells in Diet-Induced Obesity
Authors: Jason Hellmann, Petra Haberzettl, Laura Wheat, Daniel J Conklin, Timothy E O’Toole, Aruni Bhatnagar
Journal: Circulation (2009)

Chronic diabetes increases cardiovascular disease risk. Long-term hyperglycemia in diabetes increases non-glycolytic consumption of glucose via the polyol pathway, which has been linked to the development of secondary diabetic complications. To examine the contribution of this pathway, wild-type (WT; C57BL/6) mice and mice deficient in aldose reductase (AR-null), an enzyme catalyzing the first step of the pathway, were fed normal chow (NC, 13.5 % kcal fat) or a high-fat diet (HFD, 42% kcal fat) for 12 weeks. In comparison with WT mice (n=12), AR-null (n=12) mice gained significantly more weight (+14.9±0.9 g vs. +20.8±1.1 g; P&lt;0.05) and displayed greater increase in plasma cholesterol (+133±213 mg/dl vs. +194±17 mg/dl; P&lt;0.05) and insulin (+0.40±0.11 vs. +0.57±0.07 ng/ml; P&lt;0.05). Insulin (100 nM) exposure increased Akt phosphorylation in isolated aorta of WT NC mice but not of AR-null mice (see figure ). Aorta isolated from HFD WT and AR-null mice were insulin-insensitive. High-fat feeding decreased acetylcholine-induced relaxation of aorta measured ex vivo in AR-null mice by 25±4 % (P&lt;0.05, n=12) but not in WT mice. High fat feeding decreased the levels of Sca + /Flk + endothelial progenitor cells (EPCs) in the peripheral blood (per 50,000 events: 197±79 vs. 103±19; P&lt;0.05) yet increased EPCs in spleen (812±456 vs. 2088±1173; P&lt;0.05) and bone marrow (432±269 vs. 1031±658; P&lt;0.05) in WT mice. These changes were absent in AR-null mice. Collectively, these data suggest that AR-dependent metabolism during pre-diabetic conditions plays a significant role in the maintenance of endothelial health perhaps through impaired insulin signaling and trafficking of EPCs.