tbuckley/cabot-search huggingface dataset:
Abstract 4929: Injection of Human Neural Stem Cell Line in a Mouse Hind Limb Ischemia Model Promotes Muscle Neovascularisation
Authors: Rajesh Katare, Erik Miljan, Randolph Corteling, Caroline Hicks, Costanza Emanueli, John Sinden, Paolo Madeddu
Journal: Circulation (2009)

Objective: Recently, the human conditionally immortalized neural stem cell (hNSC) line, CTX0E03, has received approval from the UK MHRA for treatment, by direct intracerebral implantation, of stable stroke disability in elderly patients. We report here for the first time that intramuscular injection of the CTX0E03 hNSC line into a mouse model of hind-limb ischemia results in a repeatable significant, dose-dependent therapeutic improvement in blood flow. Methods: Unilateral limb ischemia was induced in immunodeficient (FoxnCD1 nu/nu ) mice. Suspensions of CTX0E03 cells were administered by injection into the ischemic limb adductor muscle. Five different doses of hNSCs were tested in two experiments (3 million; 1 million; 300,000 in Exp 1 and 300,000, 30,000 and 3,000 in Exp 2), with vehicle injections used as a control in both experiments (n=10/group). Laser Doppler measurements of the limbs were taken at Days 3, 7, 14 and 21. Capillary and arteriole density and absolute blood flow measurements (0.02 μ m fluorescent microspheres) were done on Day 21. Results: The three highest doses of CTX0E03 cells markedly increased the recovery of blood flow to the ischemic limb as measured by Doppler (Figure A ), adductor muscle blood flow (Figure B ) and capillary and arteriole density. The two lower doses, 30,000 and 3,000 cells produced no significant improvements. Histological analysis demonstrated CTX0E03 cell survival at Day 21 in some, but not all, of the implanted muscles. Conclusion: CTX0E03 cell therapy significantly improved clinically relevant aspects of hind limb ischemia in nude mice dose dependently by enhancing neovascularization.
Abstract 5091: Long-Term Clinical Outcome of Therapeutic Angiogenesis by Autologous Transplantation of Bone Marrow Mononuclear Cells for Patients With Chronic Limb Ischemia - Results of the TACT Trial, Prognosis, Efficacy and Safety
Authors: Satoaki Matoba, Hiroaki Matsubara, Tsutomu Imaizumi, Toyoaki Murohara, Yoshihiko Saito, Masanori Fukushima
Journal: Circulation (2009)

Therapeutic Angiogenesis by Cell Transplantation (TACT) study is the first randomized controlled angiogenic cell therapy by intramuscular injection of autologous bone marrow mononuclear cells (BM-MNCs) in the patients with critical limb ischemia. The feasibility of TACT was reported in the Lancet (2002). Objective and Results The present study was designed to assess the 3-year safety and clinical outcomes of this angiogenic cell therapy by investigating the mortality and leg amputation-free interval as primary endpoints. Three year overall survival rates were 80% in patients with peripheral artery disease (PAD) (11 died in 74 patients) and 100% (no death) in 41 patients with thromboangiitis obliterans (TAO, Buerger’s disease). Three-year amputation-free rate was 60% in PAD and 91% in TAO patients (Fig ). These mortality and amputation-free rate were lower than the historical data from the conventional therapies. The multi-variate analysis revealed that the severity of rest pain and repeated experience of bypass surgery are the prognostic factors negatively affecting amputation-free interval. The significant improvement in the rest pain, ulcer size and walking distance was maintained during at least 2 year after the therapy. Conclusions The present study demonstrates that the angiogenic cell therapy using BM-MNCs has an ability to induce a long-term efficient increase in the regional perfusion in ischemic limbs, leading to extension of amputation-free interval. The safety and efficacy are superior to the conventional revascularization therapies. The severity of rest pain and the history of bypass surgery negatively influence the responsiveness to this cell therapy.
Abstract 4851: Three-year Target Systolic Blood Pressure Less Than 120 mmHg for More Than 65 Aged Hypertension Patients With Chronic Renal Disease
Authors: Xianghong Zeng, Yunyun Li, Xianghong Zeng, Zhaohuan Liu, Xiangji Zeng, Xiaoyun Chen
Journal: Circulation (2009)

Background: Many studies demonstrate that systolic blood pressure (SBP) ≥140 mm Hg does not provide renal protection in renal disease with hypertension, but SBP≤120 mmHg may be able to slow progress of renal disease. However, target SBP≤150 mmHg in elderly hypertension patients was recommended in Chinese hypertension guideline in 2005.The safety and efficacy of SBP≤120 mmHg in elderly hypertension patients with chronic renal disease is hardly reported. Methods: In a prospective, controlled open-label studies, the authors have evaluated the safety and efficacy of three-year treatment on progress of renal disease and risk of development of cardiovascular disease in 122 &gt;65 aged hypertension patients with chronic renal disease. Before randomization, all patients have already been treated for one-year with angiotensin converting enzyme inhibitors (ACEI) or angiotensin AT 1 receptor blockade(ARBs) and other antihypertensive drugs, but their SBP are above 140 mmHg but less than 150 mmHg. Blood pressure, serum creatinine(Cr) and potassium were monitored every 14 days in the period of follow-up.. Results: By the end of three years, Cr clearance increased from 51±2.0 to 63±3.2 ml/min, p&lt;0.001,in the group of strict control of SBP, By contrast, Cr clearance decreased significantly from 52±1.9 to 42±2.1 ml/min, P&lt;0.01, in the controls. During this time, urine protein excretion decreased from 1.4±0.5 to 0.4±0.4g every 24 hours (P&lt;0.01) in the treatment group, but urine protein excretion decreased slightly (from 1.3±0.4 to 1.2±0.5, P&gt;0.05) in the controls. Nine patients had got ACS, 10 patients stroke, three patients died in SCD and 2 patients died in chronic heart failure in controls but one patient had ACS, two patients stroke, one died in non-cardiac cause and 2 patients had mild dizzy who can continue to take theses drugs in the treatment group(p&lt;0.01).However, the incidence of hyperkalaemia was similar between two groups. Conclusions: Long-term SBP≤120 mmHg is safe and was more apparently in decreasing proteinuria, slowing the progress of renal disease and reducing the risk of development of acute cardiovascular events in elderly hypertensive patients with chronic renal disease.
Abstract 5197: Arterial Remodeling Determines the Local Hemodynamic Environment and Subsequent Progression of Coronary Atherosclerotic Plaques: A Serial, Natural History Intravascular Ultrasound Study
Authors: Konstantinos C Koskinas, Yiannis S Chatzizisis, Ahment U Coskun, Michael Jonas, Aaron Baker, Elazer R Edelman, Charles L Feldman, Peter H Stone
Journal: Circulation (2009)

Background Endothelial shear stress (ESS) is a critical determinant of plaque formation and arterial remodeling. Expansive remodeling is a feature of plaque vulnerability. Our purpose was to assess the role of remodeling and ESS in plaque progression throughout the natural history of atherosclerosis. Methods Intravascular ultrasound (IVUS)-based 3D reconstruction of all major coronary arteries (n=15) was performed in vivo at weeks 4, 11, 16, 23 and 36 in five diabetic, hyperlipidemic pigs. Each artery was divided into 3mm-long segments (n=304). We calculated ESS in all segments at all time points using computational fluid dynamics. Remodeling was characterized at all time points as excessive expansive, compensatory or constrictive. Plaque progression between consecutive time points was assessed by change of plaque area (ΔPlaque). Results The remodeling response to individual plaque formation changed substantially over time. Excessive expansive remodeling persistently developed in regions of very low ESS (Fig A ), further decreased the low ESS (p&lt;0.05), and was associated with the most marked additional plaque growth (Fig B ). Compensatory and constrictive remodeling generally resulted in increase of local ESS, and in less pronounced plaque progression (Fig A, B ). Conclusions This study provides new insight into the role of remodeling as a determinant of plaque progression. Excessive expansive remodeling exacerbates the pro-atherogenic low ESS environment, and promotes subsequent plaque growth. In contrast, attenuation of the low ESS stimulus occurs in lesions that elicit a compensatory, or constrictive remodeling response, leading to relative plaque quiescence.
Abstract 5171: High Levels of Myeloid-related Protein 14 in Human Atherosclerotic Plaques Correlate With the Characteristics of Rupture-prone Lesions
Authors: Mihaela G Ionita, Aryan Vink, Esme Dijke, Jon Laman, Wouter Peeters, Jean Paul de Vries, Frans Moll, Gerard Pasterkamp, Dominique de Kleijn
Journal: Circulation (2009)

Objective : Atherosclerotic plaque rupture can lead to severe complications such as myocardial infarction and stroke. Myeloid related protein (Mrp)-14, Mrp-8 and Mrp-8/14 complex are inflammatory markers associated with myocardial infarction. It is, however, unknown if Mrps are associated with a rupture-prone plaque phenotype. In this study, we determined the association between Mrp-14, -8, -8/14 plaque levels and plaque characteristics. Methods and Results : In 186 human carotid plaques, levels of Mrp-14, -8 and -8/14 were quantified using ELISA. High levels of Mrp-14 were found in lesions with a large lipid core, high macrophage staining and low smooth muscle cell and collagen amount. Plaques with high levels of Mrp-14 contained high interleukin (IL)-6, IL-8, matrix metalloprotease (MMP)-8, MMP-9 and low MMP-2 concentrations. Mrp-8 and Mrp-8/14 showed a similar trend. Within plaques, a subset of non-foam macrophages expressed Mrp-8 and Mrp-14 and the percentage of Mrp-positive macrophages was higher in rupture-prone lesions compared to stable ones. In vitro , this subset of macrophages does not acquire a foamy phenotype when fed with human oxidized low density lipoprotein (oxLDL). In contrast, the vast majority of macrophages lacking Mrp-8/14 membrane expression accumulated lipid droplets in the cytoplasm when fed with oxLDL. Conclusion : High levels of Mrp-14 and to a lesser extent also Mrp-8 and Mrp-8/14, expressed by a subset of non-foam macrophages in human plaques, are strongly associated with both histopathological features and the inflammatory status of rupture prone lesions. These results identify Mrps as possible imaging markers to detect the hidden rupture-prone plaque.
Cyclophilin A Augments ROS Production and Angiotensin II–Induced Cardiac Hypertrophy in Mice
Authors: Kimio Satoh
Journal: Circulation (2009)

Abstract #3090 Kimio Satoh, Dept of Cardiovascular Med, Tohoku Univ Graduate Sch of Med, Sendai, Japan; Patrizia Nigro, Fabrice Jaffré, Michael R. O’Dell, New New Soe, Zhaoqiang Cui, Amy Mohan, Burns C. Blaxall, Bradford C. Berk, Aab Cardiovascular Res Inst and Dept of Med, Univ of Rochester, Rochester, NY Kimio Satoh, 2009 Finalist and Presenting Author
Abstract 4891: Angiotensin II-activated Caspase 3-dependent Apoptosis in the RVLM Contributes to Sympathoexcitaion Through the Activation of Ras/MAPK/ERK Pathway
Authors: Takuya Kishi, Yoshitaka Hirooka, Kenji Sunagawa
Journal: Circulation (2009)

Background: The rostal ventrolateral medulla (RVLM) regulates sympathetic nerve activity (SNA). Angiotensin II-derived superoxide anion in the RVLM induces the pressor response via the activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). Small G protein Ras mediates caspase 3-dependent apoptosis through the activation of p38 MAPK and ERK. We hypothesized that angiotensin II/angiotensin II type 1 receptor (AT 1 R)-activated caspase 3-dependent apoptosis in the RVLM contributes to sympathoexcitation through the activation of Ras/p38 MAPK/ERK pathway in stroke-prone spontaneously hypertensive rats (SHRSP). Methods and Results: Telemetrically measured mean blood pressure (MBP) and heart rate (HR) under a conscious state, and SNA assessed by urinary norepinephrine excretion, were significantly higher in SHRSP than in Wistar-Kyoto (WKY) rats. Activities of Ras, p38 MAPK, ERK, and caspase 3 in the RVLM were significantly higher in SHRSP than in WKY (Ras; 1.7 ± 0.2 U vs 1.3 ± 0.2 U, p38 MAPK; 1.8 ± 0.1 U vs 1.2 ± 0.3 U, ERK; 2.1 ± 0.3 U vs 1.4 ± 0.3 U, caspase 3; 1.7 ± 0.1 U vs 1.1 ± 0.2 U, n = 5 for each, P &lt; 0.01). Mitochondrial apoptotic proteins Bax and Bad in the RVLM were also significantly increased in SHRSP (Bax; + 38 ± 2%, Bad; + 43 ± 3%, n = 5 for each, P &lt; 0.01). In SHRSP, intracerebroventricular (ICV) infusion of Ras inhibitor, Z-DEVD-FMK, significantly reduced MBP, HR, and SNA (MBP; −38 ± 4mmHg, HR; −44 ± 18bpm, SNA; −0.8 ± 0.2 μ g/day, n = 5 for each, P &lt; 0.01) and inhibited activities of Ras/p38 MAPK/ERK, Bax, Bad, and caspase 3 in the RVLM (Ras; −36 ± 3%, p38 MAPK; −27 ± 3%, ERK; −24 ± 2%, Bax; −21 ± 3%, Bad; −28 ± 5%, caspase 3; −39 ± 6%, n = 5 for each, P &lt; 0.01). ICV of caspase 3 inhibitor also decreased MBP, HR, and SNA in SHRSP. ICV of AT 1 R blocker, candesartan, in SHRSP decreased MBP, HR, and SNA (MBP; −34 ± 5mmHg, HR; −52 ± 14bpm, SNA; −0.9 ± 0.2 μ g/day, n = 5 for each, P &lt; 0.01) and reduced activities of Ras/p38 MAPK/ERK, Bax, Bad, and caspase 3 in the RVLM. Conclusion: Angiotensin II/AT 1 R-activated caspase 3-dependent apoptosis in the RVLM increases SNA through the activation of Ras/p38 MAPK/ERK pathway in SHRSP. This mechanism of sympathoexcitation may play a crucial role in the pathogenesis of hypertension.
Abstract 5040: Antioxidative Treatment in Salt Loaded Zucker Diabetic Fatty Rats Prevents Vascular Hypertrophy
Authors: Markus Resch, Sabine Fredersdorf, Christoph Birner, Peter Schmid, Christian Schach, Günter A Riegger, Andreas Luchner, Dierk H Endemann
Journal: Circulation (2009)

Vascular hypertrophy of resistance arteries is an early form of end-organ damage. In this study we test whether antioxidative treatment by inhibition of distinct sources of oxidative stress (namely NADPH oxidase and mitochondria) improves vascular remodeling and thereby reduces end-organ damage in diabetes mellitus (DM) associated with salt sensitive hypertension. As a model of type 2 DM Zucker Diabetic Fatty (ZDF) rats receiving high salt (5.5%) diet were divided into 3 groups receiving no antioxidative treatment (ZDF+S) or treated with inhibitors of sources of oxidative stress with apocynin (inhibitor of the NADPH oxidase) (ZDF+S+A) or with PJ-34 (PARP-inhibitor) (ZDF+S+PJ) for 6 weeks. Euglycemic Zucker lean (ZDL) rats served as controls. Systolic blood pressure (SBP) was measured weekly by tail cuff method. MRNA expressions of p22phox as a subunit of NADPH oxidase were quantified by RT-qPCR in mesenteric resistance arteries. Vascular hypertrophy (media to lumen ratio, M:L) and passive mechanical stiffness of mesenteric resistance arteries were assessed using a pressurized myograph. SBP was significantly higher in ZDF+S compared to ZDL (ZDF+S: 144±1; ZDL: 134±3 mmHg; p&lt;0.05). There was no relative effect of antioxidative treatment on serum glucose levels and SBP (ZDF+S+A: 142±1; ZDF+S+PJ: 145±2 mmHg). M:L of mesenteric arteries was significantly increased in ZDF+S vs ZDL (5.8±0.3 vs 4.7±0.1; p&lt;0.05) indicating marked vascular hypertrophy. Antioxidative treatment significantly prevented vascular hypertrophy by inhibition of NADPH oxidase with apocynin (M:L in ZDF+S+A: 4.4±0.2; p&lt;0.05 vs ZDF+S) and by PARP-inhibition with PJ-34 (M:L in ZDF+S+PJ: 4.5±0.1; p&lt;0.05 vs ZDF+S). Levels of p22phox were increased in ZDF+S vs ZDL (1.7±0.2 vs 1.3±0.2). Antioxidative treatment decreased the expression of p22phox (ZDF+S+A: 1.3±0.1; ZDF+S+PJ: 1.4±0.1). Antioxidative treatment did not change vascular strain indicating no effect on vascular stiffness. Antioxidative treatment with an inhibitor of NADPH oxidase and with a PARP-inhibitor prevented vascular hypertrophy in salt loaded ZDF rats without changing blood pressure levels. Thus, targeted inhibition of sources of oxidative stress may be of importance to prevent end-organ damage in diabetes.
Abstract 5440: Forward Programming of Pluripotent Stem Cells Towards Distinct Cardiovascular Cell Types
Authors: Robert David, Juliane Stieber, Evelyn Fischer, Stefan Brunner, Christoph Brenner, Susanne Pfeiler, Florian Schwarz, Wolfgang-Michael Franz
Journal: Circulation (2009)

Aims: The proliferative potential of pluripotent stem cell derived cardiomyocytes is limited and reasonable yields for novel therapeutic options have yet to be achieved. In addition various clinical applications will require the generation of specific cardiac cell types. Whereas early cardiovascular precursors appear to be important for novel approaches such as reseeding decellularized hearts, direct cell transplantation may require ventricular cells. Our recent work demonstrated that MesP1 represents a master regulator sufficient to induce cardiovasculogenesis in pluripotent cells. This led to our hypothesis that “forward programming” towards specific subtypes may be feasible via overexpression of distinct early cardiovascular transcription factors. Methods and results: Here we demonstrate that forced expression of Nkx2.5 similar to MesP1 is sufficient to enhance cardiogenesis in murine embryonic stem cells. In comparison to control transfected mES cells a 5 fold increased appearance of beating foci was observed as well as upregulated mRNA and protein expression levels. In contrast to MesP1 no increase of the endothelial lineage within the cardiovasculogenic mesoderm was observed. Likewise Flk-1, the earliest known cardiovascular surface marker was not induced via Nkx2.5 as opposed to MesP1. Detailed patch clamping analyses showed electrophysiological characteristics corresponding to all subtypes of cardiac ES cell differentiation in Nkx2.5 as well as MesP1 programmed embryoid bodies (EBs) but fractions of cardiomyocytes had distinct characteristics: MesP1 forced the appearance of early/intermediate type cardiomyocytes in comparison to control transfected ES cells whereas Nkx2.5 led to preferentially differentiated ventricular cells. Conclusion: Our findings show proof of principle for cardiovascular subtype specific programming of pluripotent stem cells and confirm the molecular hierarchy for cardiovascular specification initiated via MesP1 with differentiation factors such as Nkx2.5 further downstream.
Abstract 4196: Effect of 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitors (Statins) on Renal Function
Authors: Rishi Sukhija, Zoran Bursac, Bhavna Mohandas, Rajesh Sachdeva, Luis Garza, Y W Aude, Anjan K Sinha, Jawahar L Mehta
Journal: Circulation (2006)

Background: 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) reduce serum cholesterol, and cardiovascular morbidity and mortality. The role of lipids in the progression of kidney disease and the potential beneficial effects of statins on renal function is unknown. Oxidative stress and inflammation may be the missing link between CAD and chronic kidney disease. Statins may protect the kidney through both lipid lowering properties and pleiotropic effects. Methods: We analyzed data in 197, 551 patients (mean age 64.8±13.6 years, 95% males, 29.5% (58,332) statin users, and 70.5% (139, 219) non-statin users), who had baseline creatinine less than 3.5 mg/dl, from the cross-sectional data mined from the Veterans Affairs VISN 16 database. Deterioration of renal function was defined as doubling of the baseline or increase in creatinine of 0.5 mg/dl over at least 90 days. Results: Based on this definition, 3.4% of patients developed renal deterioration over 5 year of follow-up. After adjustment for demographics, diabetes mellitus, smoking, and other medications (especially use of angiotensin-converting enzyme inhibitors, calcium channel blockers and aspirin, all of which were confounders of the statin-renal deterioration relationship), use of statins reduced the odds of deterioration in renal function by 15% (OR 0.85, 95% CI=0.80 – 0.89, p&lt;0.0001). This effect was independent of cholesterol lowering effect of statins. Impact of other variables was as follows: age (OR=1.04, CI=1.03–1.04, p&lt;0.0001), diabetes (OR=1.76, CI=1.67–1.85, p&lt;0.0001), and smoking (OR=1.76, CI=1.05–1.23, p=0.0014). Conclusion: Statin use may retard the progression of renal disease. Although the precise mechanism is not known, lowering of LDL-cholesterol and improvement in endothelial function by statins may relate to reno-protective effect.
Abstract 5162: Inhibition of Interleukin-6 Transsignaling Suppresses Atherosclerotic Lesion Development
Authors: Harald Schuett, René Schley, Gustavo Salguero, Uwe J Tietge, Georg H Waetzig, Dirk Seegert, Stefan Rose-John, Karsten Grote, Bernhard Schieffer
Journal: Circulation (2009)

Introduction: The inflammatory cytokine interleukin-6 (IL-6) is a central mediator in the pathophysiology of various acute and chronic inflammatory disorders e.g. sepsis, Crohn disease or rheumatoid arthritis. Of interest, mainly the IL-6 transsignaling which comprises binding of IL-6 to the soluble IL-6 receptor (sIL-6R) and subsequent signal transduction as an IL-6/sIL-6R complex via ubiquitary expressed gp130 plays a pivotal role in these processes. Since atherosclerosis is likewise characterized by chronic vascular inflammation we here investigated the impact of IL-6 transsignaling on atherosclerotic plaque development in a murine model. For this reason, we used the fusion protein sgp130Fc which competitively binds to the IL-6/sIL-6R complex and thus specifically inhibits the IL-6 transsignaling. Methods and results: Initial in vitro experiments confirmed that recombinant sgp130Fc was able to inhibit the IL-6-induced STAT-3 phosphorylation in primary murine aortic vascular smooth muscle cells and murine monocytic RAW 264.7 cells dose-dependently (VSMC maximal at 10 μ g/ml; RAW maximal at 50 μ g/ml, Western blot, P&lt;0.05). IL-6 induced the migration and proliferation of VSMC in vitro which could be inhibited by sgp130Fc (transwell inserts, BrdU-incorporation, −30%, P&lt;0.05). Migration of RAW cells was likewise suppressed when IL-6 transsignaling was abrogated by sgp130Fc pre-treatment (transwell inserts, −40%, P&lt;0.05). Finally, male atherosclerosis-prone LDLR −/− mice on a cholesterol rich diet were treated with sgp130Fc (0.5 mg/kg/bw i.p., twice-weekly) or the respective vehicle for 8 and 16 weeks. Even though serum lipid levels were unchanged, sgp130Fc administration led to a dramatically decreased atherosclerotic plaque development (thoracoabdominal aorta −65%/aortic root −35%; oil red O staining, P&lt;0.05, n=5–9) as well as a reduced monocyte invasion into the vessel wall (aortic root −35%; MOMA-2 immunostaining, P&lt;0.05, n=5–9). Conclusion: We here demonstrate - for the first time - that inhibition of the IL-6 transsignaling by the pharmacological compound sgp130Fc suppresses pro-atherosclerotic processes and subsequently the development of atherosclerotic plaques.