bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5141: Guanylyl Cyclase Activation Using HMR1766 Improves Endothelial Function and Reduces Platelet Activation in Congestive Heart Failure
Authors: Schaefer Andreas , Fraccarollo Daniela , Bauersachs Johann 
Published: April 2024

Background: Endothelial dysfunction and platelet activation are part of the cardiovascular phenotype of severe congestive heart failure(CHF). An association between reduced endothelium-dependent NO-bioavailability and platelet activation has been described in experimental CHF. We investigated, whether chronic activation of soluble guanylyl cyclase using HMR1766 increases vascular NO-bioavailability and reduces platelet activation in experimental CHF.
Methods and results: Chronic myocardial infarction was induced in male Wistar rats by coronary ligation. Rats were randomised to placebo or HMR1766 (10mg/kg twice daily). After 10 weeks, haemodynamics were measured and endothelial function was assessed in organ bath studies. Only animals were included in the CHF groups, when left-ventricular infarct size was >45% and left-ventricular end-diastolic pressure was >15 mmHg. Endothelium-dependent, acetylcholine-induced and NO-mediated relaxation of the aorta was significantly attenuated in CHF-Placebo compared to Sham-operated rats (Rmax: Sham 83.9±1.4%, CHF-Placebo 56.9±5.9%, p<0.01) and markedly improved in CHF-HMR1766 (Rmax 75.4±4.6% p<0.01 vs. CHF-Placebo). Basal NO-bioavailability in vivo was determined by the extent of phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets from whole blood fixed in formaldehyde immediately following collection. Platelet in vivo-VASP phosphorylation was attenuated in CHF-Placebo compared to Sham animals (mean fluorescence intensity: Sham 16.4±1.0%, CHF-Placebo 13.4±0.3%, p<0.05), and normalised by HMR1766 treatment (17.1±1.2% p<0.05 vs. CHF-Placebo). Activation of circulating platelets was determined measuring P-selectin surface-expression on platelets by flow-cytometry. P-selectin surface-expression was significantly increased in CHF-Placebo (mean fluorescence intensity: Sham 14.2±0.4%, CHF-Placebo 16.0±0.4%, p<0.05) and reduced following treatment with HMR1766 (14.5±0.3% p<0.05 vs. CHF-Placebo).
Conclusion: Chronic guanylyl cyclase activation using HMR1766 significantly improved endothelial function, enhanced systemic NO-bioavailability and reduced platelet activation in CHF rats.
Abstract 5161: Accelerated Telomere Shortening in CD8+ T-lymphocytes From Patients With Coronary Heart Disease Links Cytomegalovirus-Induced T Cell Response and Deterioration of Myocardial Function
Authors: Hoffmann Jedrzej , Brümmendorf Tim , Aicher Alexandra , Zeiher Andreas M , Dimmeler Stefanie M , Spyridopoulos Ioakim 
Published: April 2024

Shortening of mean telomere length (TL) in white blood cells is correlated with the development of coronary heart disease (CHD) as well as with increased mortality due to infectious disease. The goal of this study was to investigate whether TL shortening in CHD is restricted to specific peripheral blood lymphocyte and/or myeloid cell subpopulations. Results were correlated to TL in CD34+ hematopoietic peripheral blood stem and progenitor cells (PBPC) obtained from the same patients. TL was measured by Multicolor Flow-FISH in 12 leukocyte subpopulations following immunomagnetic bead sorting. We investigated TL in 14 young (mean age 25 years) and 13 old healthy male volunteers (65 years), as well as in 25 age-matched patients (65 years) suffering from CHD. We show that TL in granulocytes and monocytes mirrors TL of CD34+ PBPC extremely well (r=0.95; p<0.0001), in patients as well as in healthy adults. TL was approximately 500 base pairs shorter in leukocytes from patients with CHD compared to their age-matched controls. This difference was identical for CD34+ PBPC, monocytes, granulocytes, B-lymphocytes and CD4+ T-cells. Surprisingly, only in cytotoxic CD8+ T lymphocytes (CTL), we found a substantially increased TL deficit of 1000 bp (p<0.001 vs. CD4+ cells) in CHD patients as opposed to controls. Further analysis revealed that TL shortening was particularly pronounced in CD8+CD28− T-cells obtained from cytomegalovirus (CMV) seropositive CHD patients, whereas such a difference was not observed in healthy CMV positive as opposed to CMV negative controls. Moreover, TL shortening of CD8+CD45RA+ T-cells from CMV seropositive patients correlated with the decrease of left ventricular function in CHD patients (r=0.635, p=0.001). In contrast, CMV seropositivity did not have any influence on TL in myeloid cells or PBPC.
Conclusion: Our data suggest that TL shortening in CHD is inherited, thus affecting the baseline TL of all peripheral blood cell populations including PBPC. In addition, CMV seropositive patients exhibit further shortening of their CTLs. Surprisingly, telomere length shortening of CTLs in CMV seropositive individuals demonstrated a very strong correlation with cardiac dysfunction, suggesting a mechanistic link between CHD and immunosenescence.
Abstract 5281: Novel Role of p66shc in ROS-dependent VEGF Signaling and Cell-Cell Adhesions in Endothelial Cells
Authors: Oshikawa Jin , McKinney Ronald , Fukai Tohru , Ushio-Fukai Masuko 
Published: April 2024

p66shc is an adaptor protein and functions as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. We demonstrated that VEGF stimulation rapidly increases ROS via activation of NADPH oxidase, which are involved in VEGF receptor 2 (VEGFR2) autophosphorylation as well as endothelial cell (EC) proliferation and migration. However, the role of p66shc in VEGF signaling has not been investigated. Here we show that VEGF stimulation increases serine phosphorylation of p66shc at Ser36 in ECs (3.1-fold at 5mins, 5.4-fold at 15mins). Adenovirus-mediated transfer of mutant p66shc (S36A) or knockdown of p66shc with siRNA decreases both basal- and VEGF-stimulated ROS levels, which results in inhibiting VEGF-induced VEGFR2 autophosphorylation (43.6% and 64.9%, respectively) as well as phosphorylation of p38MAPK (20.2% and 58.5%) and Akt (57.7% and 76.8%). Functionally, p66shc siRNA or overexpression of p66shc (S36A) inhibits VEGF-induced EC migration (58.6% and 50.9%) and proliferation (86.2% and 100%). Of note, immunofluorescence analysis reveals that p66shc is colocalized with and binds to VE-cadherin/beta-catenin complex at cell-cell contacts in confluent ECs, which is required for stabilizing cell-cell adhesions. Depletion of p66shc with siRNA disrupts VE-cadherin-beta-catenin complex, thereby reducing VE-cadherin localization at adherens junction and increasing endothelial permeability (40.8% increase), as measured by transendothelial electric resistance. Moreover, p66shc siRNA markedly reduces basal- and VEGF-stimulated stress fiber formation, which may contribute to a mislocalization of VE-cadherin. In summary, p66shc functions as a key regulator for ROS-dependent VEGF signaling linked to angiogenesis and actin reorganization as well as stabilizing cell-cell junctions. Thus, p66shc is a potential therapeutic target for 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 & Wisconsin).
Abstract 5334: Association Between Hospital Process Performance and 1-Year Post-discharge Mortality in Patients With Non-ST-elevation Myocardial Infarction: Results From 36,262 Patients
Authors: Shah Bimal R , Roe Matthew T , Chen Anita Y , Alexander Karen P , Wang Tracy Y , Ohman E. Magnus , Gibler W. Brian , Peterson Eric D 
Published: April 2024

Background: While hospitals’ adherence to performance measures for evidence-based NSTEMI care has been associated with better in-hospital outcomes, its association with long-term mortality is unknown.
Methods: Clinical data from CRUSADE were matched to Medicare claims, creating a longitudinal record of outcomes for patients aged >=65 years. Cox proportional hazard modeling was used to examine the association between 1-year post-discharge mortality and hospital composite adherence to 9 Class I ACC/AHA guideline therapies (antiplatelet, beta-blocker, any heparin, and GP IIB/IIIA within 24 hours; antiplatelet, beta-blocker, clopidogrel, ACEI/ARB, and lipid-lowering agent at discharge).

Results: Between February 19, 2003, and December 31, 2006, 36,262 NSTEMI patients treated at 268 CRUSADE hospitals were linked to Medicare data. The median hospital composite performance adherence score was 81% and varied widely (lowest to highest quartile: 73%, 79%, 83%, and 88%). Greater composite performance adherence was strongly associated with reduction in 1-year mortality. The observed 1-year mortality rate was 21%. Unadjusted mortality rates were 24%, 22%, 19%, and 19% in the lowest to highest hospital adherence score quartiles. This association persisted after adjusting for baseline clinical factors and additionally for revascularization (p<0.001 between highest and lowest hospital adherence score quartiles for all hazard ratios) (Figure

).

Conclusion: Hospital adherence to ACC/AHA AMI guideline therapies is strongly associated with improved long-term mortality, further supporting the use of these metrics for measuring and improving AMI. care.
Abstract 5427: Regulation of Arterial Branching Morphogenesis by Notch Ligand Delta-like 1
Authors: Limbourg Florian P , Woiterski Jeanette , Augustynik Michael , Napp L C , Limbourg Anne , Drexler Helmut 
Published: April 2024

Arterial development and homeostasis are regulated by genetic factors and hemodynamic forces but how hemodynamic forces shape arterial branching morphogenesis and whether there is cross-talk to genetic programms is largely unknown. Here we show that the Notch ligand Delta-like 1 (Dll1) is regulated by hemodynamic forces to regulate arterial branching morphogenesis and adult arterial phenotype in vivo.
RESULTS: The onset of Dll1 expression was observed in fetal arteries at embryonic day E12.5, concurrent with the establishment of proper arterial circulation. Dll1 expression was restricted to endothelial cells (EC) of arteries and absent in veins or capillaries. Arterial branching morphogenesis in the developing retinal vasculature was significantly reduced in Dll1+/− mice, which lacked arterial branches forming the secondary vascular plexus. To test the influence of hemodynamic forces on Dll1 expression we exposed human aortic EC to cyclic stretch in vitro (10 and 15%), which upregulated Dll1 mRNA and protein levels and activated Notch target gene expression of Hes1 in a time-dependent manner. Dll1 regulation by hemodynamic forces had a strong impact on the branching phenotype of adult coronary arteries. Whole-mount ink perfusion and SMA-stained ventricular cross sections demonstrated significant rarefication of small, medium and large coronary arteries of Dll1+/− mice (p<0.01), while the number of microvessels was significantly increased (p<0.01). Quantification of the perfusion territory of the left descending coronary artery (LAD) by Evans blue perfusion revealed a significantly reduced perfusion territory in Dll1+/− mice (37±5% of wt, p<0.01), consistent with a regulation of coronary branching and extension by Dll1. Notably, while body size was normal, heart weight and LV dimensions were reduced in Dll1+/− mice, but EF was increased to maintain a normal stroke volume and cardiac output. To test whether hemodynamic forces regulate Dll1 expression in vivo we occluded the LAD and performed Dll1 stainings in sections 24hrs after occlusion, which revealed downregulation of EC Dll1.
CONCLUSION: Hemodynamic forces regulate Dll1 which regulates arterial branching morphogenesis during development and postnatal life.
Abstract 5441: Critical Role of Increased MicroRNA-126 Expression for the Pro-angiogenic Capacity of Autologous Human CD34+ Stem/Progenitor Cells
Authors: Mocharla Pavani , Briand Sylvie , Giannotti Giovanna , Doerries Carola , Lüscher Thomas F , Landmesser Ulf 
Published: April 2024

Circulating, bone-marrow derived CD34+ progenitor cells have been shown to promote ischemia-induced neovascularisation, and are currently explored as a potential novel therapeutic strategy in ischemic heart disease. By using culture approaches “early” endothelial progenitor cells (EPCs) are thought to be derived from CD34+/CD14+ cells, whereas “late outgrowth” EPCs are thought to be derived from CD34+/CD14− cells. The aim of the present study was to determine the expression of pro- and anti-angiogenic microRNAs in CD34+ cells and to characterize their role for endothelial growth promoting effects.
Methods: We examined the pro- and anti-angiogenic microRNA expression profile, of circulating CD34+14+ and CD34+14− stem/progenitor cells, as compared to CD34−14+ (monocytes) and CD34−14− (lymphocytes) isolated by MACS sorting from mononuclear cells, by using quantitative RT-PCR. Furthermore, pro-angiogenic effects of these cell populations were examined by tubulogenesis in co-cultures with differentiated endothelial cells (HAECs). In vivo endothelial repair capacity was determined by cell transplantation (200,000 cells) into nude mice with carotid endothelial injury. The functional role of differentially regulated miRs was characterized by transfection with anti-miRs and miR mimics.
Results: Only CD34+14+ and CD34+14−, but not CD34−14+ or CD34−14− cells exerted a pro-angiogenic effect, paralleled by a substantially increased expression of the pro-angiogenic miR126 and miR130a. Similarly, in vivo endothelial repair was enhanced by CD34+ cells with no significant difference between CD34+14+ and CD34+14− cells. CD34+ cell transfection with anti-miR-126 abolished the pro-angiogenic effects of CD34+ cells, whereas forced expression of miR126 (miR mimic) markedly enhanced their pro-angiogenic effects.
Conclusions: These findings demonstrate for the first time a differential pro-angiogenic microRNA expression of CD34+ stem/progenitor cells as compared to CD34− mononuclear cells. Importantly expression of miR126 is critical for endothelial growth promoting effects of CD34+ cells, and represents an interesting novel target to enhance the pro-angiogenic capacity of autologous CD34+ stem/progenitor cells.
Abstract 5530: Associations Between Arterial Blood Pressure and Adipokines Expression in Subcutaneous, Femoral and Pericardial Adipose Tissue in Patients With Coronary Atherosclerosis
Authors: Bakogiannis Constantinos , Antoniades Charalambos , Tousoulis Dimitris , Antonopoulos Alexis S , Ntalarizou Evangelia , Miliou Antigoni , Psarros Costas , Triantafyllou Costas , Lymperiadis Dimitris , Stefanadis Christodoulos 
Published: April 2024

Background: Adipokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and adiponectin are synthesized in adipose tissue (AT) and may affect the development of hypertension. We characterised the synthesis of these adipokines in subcutaneous, femoral and pericardial AT of patients with advanced atherosclerosis, and we examined their impact on arterial blood pressure.
Methods: Fifty patients undergoing elective CABG (14 hypertensives 36 non-hypertensives) were recruited. Subcutaneous AT was collected from the site of CABG incision, femoral AT was collected from the area surrounding the saphenous vein (perivascular) and pericardial AT was collected from the site close to the right ventricle. AT was transferred to the lab within 30 minutes and was cultured ex-vivo for 4 hours. MCP-1, IL-6 and adiponectin were quantified in AT culture supernatants.
Results: Hypertension was associated with higher IL-6 in pericardial adipose tissue (14.7±1.8 vs 10.0±1.5 pg/mg p<0.05), MCP-1 (7.07±1.2 vs 2.7±0.6 pg/mg p<0.05) and adiponectin (229.5±15.9 vs 168.9±19.3 pg/mg, p<0.05). Importantly, hypertension was not associated with femoral IL-6 (10.9±1.3 vs 11.9±2.2 pg/mg p=NS), subcutaneous IL-6, (6.9±1.0 vs 8.4±2.1 pg/mg p=NS), femoral MCP-1 (5.7±0.8 vs 4.0±1.1 p=NS), femoral adiponectin (174±34 vs 221±26pg/mg p=NS), subcutaneous MCP-1 (2.37±0.29 vs 3.3±1.5 pg/mg p=NS) or subcutaneous adiponectin (175±18 vs 182±23.2 pg/mg p=NS) AT synthesis. Diastolic (but not systolic) blood pressure was strongly correlated with IL-6 in femoral (rho=0.492, p=0.038) and subcutaneous (rho=0.659, p=0.04) but not pericardial (rho=0.386, p=NS) AT.
Conclusions: Adipokines (IL-6, MCP-1 and adiponectin) synthesized in pericardial adipose tissue are closely associated with the presence of arterial hypertension in patients with advanced atherosclerosis. However, adipokines synthesised in femoral and subcutaneous adipose tissue are strongly associated with the variability of diastolic but not systolic blood pressure.
Abstract 5570: TRAF5 Deficiency Accelerates Atherogenesis in Mice: A Role for TRAF5 as Protective Factor in Atherosclerosis?
Authors: Missiou Anna , Varo Nerea , Rudolf Philipp , Münkel Christian , Ernst Sandra , Walter Carina , Bode Christoph , Libby Peter , Zirlik Andreas 
Published: April 2024

Background: TNF receptor associated factors (TRAFs) function as cytoplasmic adaptor proteins for cytokines of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFalpha, and IL-1beta, established mediators of atherogenesis. We recently reported over-expression of TRAFs in atheromata, TRAF-dependent inflammatory gene expression in atheromata-associated cell types, and limitation of atherogenesis in mice deficient for TRAF1. Here, we test the hypothesis that TRAF5 modulates atherogenesis in vivo.
Methods and Results: TRAF5–/LDLR– mice consuming a high cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions compared with LDLR– controls. Intimal lesion size increased by up to 328±11% and 174±15% in sections of the aortic arch and aortic root, respectively (n>13 per group, P<0.01 each). Plaques of TRAF5-deficient animals contained up to 149±15% more lipids (P<0.05) and tended to contain more macrophages and less collagen, characteristics associated with vulnerable plaques in humans. Smooth muscle cell content and lymphocyte content remained unchanged. In vitro, TRAF5-deficient endothelial cells expressed higher levels of the adhesion molecule VCAM-1 and the chemokine KC. Furthermore, TRAF5-deficient macrophages took up increased amounts of acethylated LDL (N=3). Finally, patients suffering from stable coronary heart disease and acute coronary syndrome expressed significantly lower amounts of TRAF5 mRNA in blood than healthy controls (0.026±0.0016 vs. 0.023±0.0018 vs. 0.029±0.0017 TRAF5/GAPDH mRNA, N=325, P<0.01) supporting a protective role of TRAF-5 in atherosclerosis.
Conclusions: We present the novel finding that TRAF5 deficiency accelerates atherogenesis in mice. These data identify TRAF5 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.
Abstract 5605: Significant Reduction of Hospital Mortality of Stemi in Clinical Practice 1994–2008 Through Improvement of Guideline Adherence: Results of MITRAplus and OPTAMI
Authors: Gitt Anselm K , Zeymer Uwe , Zahn Ralf , Juenger Claus , Senges Jochen 
Published: April 2024

Background: Data from national and international myocardial infarction registries have identified the gaps between recommendations of guidelines for the management of ST-elevation myocardial infarction (STEMI) and treatment in clinical practice. Participation in continuous STEMI registries with benchmarking reports to the centres might improve implementation of guidelines into practice.
Methods: Between 1994 and 2008, 37,876 consecutive patients with STEMI were enrolled into the MI-registries MITRAplus and OPTAMI to document patients’ characteristics, acute treatment and outcome in clinical practice. We examined the impact of guideline adherence for acute treatment of STEMI including reperfusion as well as adjunctive medical treatment on hospital outcome over time in Germany 1994 –2008.
Results: From 1994 to 2008, the rate of acute reperfusion therapy in Germany increased from minimal 49% to 90% of consecutive patients with STEMI in 2008 with a significant shift from fibrinolysis to primary PCI. In parallel, the use of adjunctive medical treatment with aspirin, beta-blockers, ACE-inhibitors and clopidogrel was significantly improved over time. This improvement of guideline adherence for the acute treatment of STEMI was associated with a significant reduction of hospital mortality from initially 16.2% in 1994 to 6.2% in 2008.
Limitation: In the currently conducted OPTAMI-Registry, 84% of participating centres provide 24h PCI-service. The data from 2006 –2008 therefore reflects the treatment and outcome of STEMI in tertiary centres in Germany, but clearly demonstrates that implementation of current practice guidelines is feasible.
Conclusion: The improvements of guideline adherence for the management of STEMI, especially the increased rates of primary PCI as well as acute adjunctive medical treatment were associated with a significant decrease of hospital mortality in clinical practice in Germany.
Abstract 5650: Interactions Between the Endogenous NO Synthase Inhibitor Asymmetric Dimethylarginine and the Leukocyte-derived Hemoprotein Myeloperoxidase
Authors: Sydow Karsten , von Leitner Eike-Christin , Maas Renke , Klinke Anna , Schwedhelm Edzard , Kielstein Jan T , Atzler Dorothee , Lau Denise , Ehmke Heimo , Meinertz Thomas , Willems Stephan , Böger Rainer H , Baldus Stephan 
Published: April 2024

Background: ADMA and the NO oxidizing leukocyte-derived hemoprotein MPO are associated with cardiovascular diseases. ADMA and MPO per se coincide with increased oxidative stress and induction of inflammatory responses. Furthermore, the enzymes responsible for ADMA homeostasis (i.e. dimethylarginine dimethylaminohydrolase, DDAH) are regulated in a redox-sensitive fashion. Therefore, the aim of the study was to investigate whether there is an interaction between ADMA and MPO resulting in increased leukocyte (PMN) activation and reduced NO bioavailability.

Methods: To test a direct leukocyte activating effect of ADMA, isolated human PMN were subjected to ADMA, SDMA, and fMLP -an inductor of NADPH oxidase activity- to determine PMN degranulation (MPO activity, MPO and elastase levels) and leukocyte superoxide production. NO synthase and DDAH activity was measured by GC-MS and LC-MS/MS, respectively. In vivo, the effect of chronic ADMA (250
μ
mol/kg/d; 28 days) treatment on MPO concentrations was induced by osmotic minipumps in C57 mice. To test the effect of MPO on DDAH1 and -2 gene expression, taqman rtPCR technique was performed in liver and kidney tissue of MPO knockout mice. The effect of MPO on DDAH activity in vitro was studied using a recombinant DDAH enzyme.

Results: ADMA and fMLP incubation -but not SDMA- significantly increased superoxide production, PMN degranulation and MPO release. Furthermore, ADMA but not SDMA was able to impair NO synthesis of PMN and enhanced PMN’s adhesion to cultured HUVECs in vitro. In vivo, chronic treatment with ADMA resulted in a significant increase of plasma MPO concentrations in C57 mice in contrast to vehicle-treated controls. DDAH1 gene expression was markedly increased in liver and kidney tissue of MPO knockout mice compared to C57 controls. In vitro, MPO and its product HOCl were able to impair recombinant DDAH activity, whereas inactivated MPO was not.
Summary and conclusions: ADMA profoundly activates PMN resulting in increased degranulation and MPO release, superoxide production, and impaired NO synthesis. MPO modulates DDAH expression and impairs DDAH activity. Our data revealed a two-way interaction between the ADMA and MPO pathway, which may open a new avenue for treatment of cardiovascular disease.