bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3612: Apelin Prevents Aortic Aneurysm Formation by Inhibiting Macrophage Inflammation and Infiltration
Authors: Leeper Nicholas J , Tedesco Maureen M , Kojima Yoko , Schultz Geoff , Ho Michael Y , Kundu Ramendra K , Anderson Joshua P , Tsao Philip S , Dalman Ronald L , Quertermous Thomas 
Published: July 2021

To investigate the hypothesis that Apelin treatment would attenuate aortic injury in a murine model of elastase-induced abdominal aortic aneurysm (AAA) disease, by limiting disease-related vascular wall inflammatory. Male C57BL/6 mice were implanted with osmotic mini-pumps filled with Apelin (2 mg/kg/day) or saline (Control), and subsequently treated with intra-aortic porcine pancreatic elastase to create infrarenal AAA’s. Mice were sacrificed at day 3 for aortic PCR analysis or followed ultrasonographically until day 7 and then sacrificed for histological analysis (Elastic Masson, VCAM, ICAM-1, E-Selectin, and Mac-2 semi-quantitative analysis). The cellular expression of inflammatory cytokines and chemokines in response to Apelin was assessed by TaqMan analysis of both macrophages (J774, RAW, and harvested intraperitoneal cells) and rat aortic smooth muscle cells (A7R5) and compared to other stimuli. Apelin treatment resulted in diminished AAA formation, with a 30% reduction in in vivo aortic diameter by ultrasound (1.04 mm vs 1.48 mm, p < 0.05), and a 59% reduction in maximal aortic cross-sectional area by histology (0.59 mm2 vs 1.43 mm2, p < 0.05) relative to the saline-treated group. The macrophage infiltrate also was significantly reduced in the Apelin-treated mice compared to the Control group (68.6 cells/hpf vs 285.4 cells/hpf, p < 0.001). Apelin treatment was associated with reduced mean aortic MCP-1, MIP 1-alpha, IL-6 and TNF-alpha mRNA levels, although these did not reach statistical significance. Apelin stimulation of cultured macrophage models significantly reduced MCP-1 and TNF-alpha mRNA levels compared to basal conditions (−1.12 and −1.49 fold expression change, p < 0.05, respectively). No difference in endothelial cell adhesion molecule expression or smooth muscle cell cytokine production was found in response to Apelin. Apelin significantly reduces AAA formation in this accepted model of human AAA disease. The mechanism appears to be decreased macrophage infiltration, perhaps related to an apelin-mediated decrease in pro-inflammatory cytokine and chemokine activation.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).
Abstract 3717: Receptor for Advanced Glycation End Products (RAGE) Plays an Integral Role in Non-Diabetic Atherosclerosis and Oxidized LDL Stimulation
Authors: Uekita Hironori , Ishibashi Toshiyuki , Shiomi Masashi , Sugimoto Koichi , Ohkawara Hiroshi , Kamioka Masashi , Yamagishi Shoichi , Takeishi Yasuchika 
Published: July 2021

Background: RAGE is a multifunctional receptor which identifies AGE, S100/calgranulins and HMGB-1 as the ligands. An AGE/RAGE axis plays a central role in the pathogenesis in diabetic vascular remodeling. However, the issue that hyperlipidemia associated with oxidized LDL mediates vascular responses via RAGE remains to be elucidated. In this study, we attempted to clarify the role of RAGE in non-diabetic atherosclerosis and oxidized LDL (ox-LDL) stimulation.
Methods and Results: We used the aortic and coronary atherosclerotic lesions of Watanabe heritable hyperlipidemic (WHHL) rabbits at ages of 1 to 14 months, which had high concentrations of serum ox-LDL independent of aging. Immunohistochemistry demonstrated the significant expression of RAGE as early as at age of 1 month with the stronger expression at 3 and 7 months, which was diminished at ages of 14 months. The major original sources of RAGE expression were macrophages and endothelial cells, as well as smooth muscle cells. The concentrations of serum AGE did not alter significantly with aging, while there was no difference in serum AGE level between WHHL rabbits and control New Zealand White rabbits. These data suggest the integral role of RAGE in the initiation and progression of non-diabetic atherosclerosis associated with hyperlipidemia. We further investigated the relevance of RAGE expression in a monocyte/macrophage lineage. Fluorescent immunohistochemistry and Western blotting showed the expression of RAGE on plasma membrane in isolated human peripheral monocytes, with the stronger expression in cultured monocyte-derived macrophages. Inhibition of RAGE by siRNA suppressed AGE-induced MCP-1, MMP-9 and PAI-1 expression in cultured human macrophages. Inhibition of RAGE did not significantly suppress the incorporation of DiI-labeled oxidized LDL in monocyte-derived macrophage by fluorescent study. However, oxidized LDL- triggered MCP-1, MMP-9 and PAI-1 expression was attenuated by inhibition of RAGE.
Conclusions: Our in vivo and in vitro study shows that RAGE plays an integral role in the initiation and development of atherosclerosis independent of diabetes and that ox-LDL mediates vascular responses via RAGE.
Abstract 3783: An Insulin-independent AMPK-dependent Survival Pathway Is Activated In Glucose-starved Cardiac Myocytes through IRS-1/PI3-kinase and Rictor-mediated Activation of PDK1 and PDK2
Authors: Chopra Ines , Li Huifang , Bishopric Nanette H , Webster Keith A 
Published: July 2021

INTRODUCTION: Akt (PKB) is the downstream effector of insulin and IGF-1 and regulates multiple targets that control cell survival and growth. Akt is phosphorylated at Thr-308 (activating) and Ser-473 (regulatory) sites by PI3-kinase dependent kinase-1 (PDK1) and TOR2-rictor/PDK2 respectively. When energy is abundant Akt supports cell growth by stimulating TORC1 and inhibiting GSK3β. When energy and insulin are low such as during ischemia, AMPK is activated and depresses TORC1 by activating the repressive TSC1/2 complex. It is not known how AMPK affects TORC2 in this setting.
HYPOTHESIS: Under low energy states AMPK promotes survival by differentially regulating TORC1 and 2 thereby maintaining Akt phosphorylation and survival in the absence of insulin.
METHODS: Cardiac myocytes (CM) were subjected to glucose and insulin-free incubation for 4h and the activities of insulin signaling components were measured by western blot and co-IP. Survival was measured ± siRNAs by Hoechst/PI staining.
RESULTS: After 4h of glucose/insulin deprivation there was increased phosphorylation of Akt-Thr-308 (11.2±2.4; n=6, p<0.001) and Akt-Ser-473 (9.7± 2; n=6, p<0.001). Phosphorylation of GSK-3β (Ser-9) also increased but there was decreased phosphorylation of p70S6-kinase (Thr389) and 4EBP (Ser65) indicating global down-regulation of TORC1. We identified 2 separate pathways for the insulin-independent phosphorylation of Akt at both sites in glucose-depleted CM. Activated AMPK promoted phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser-789. AraA or a Ser-789 decoy peptide blocked this, and IRS-1-P-Ser-789 co-IP’d with PI3-kinase suggesting positive regulation of PDK1. Glucose depletion did not change the levels of rictor or raptor or their relative binding to TOR. However TSC1 and rictor were quantitatively associated with PI3-kinase selectively under glucose/insulin depletion and this correlated with Akt phosphorylation. CM survival under glucose/insulin depletion was impaired by siRNA-mediated knockdown of IRS-1 or rictor (n=3; P<0.05).
CONCLUSIONS: AMPK maintains phosphorylation of Akt under low energy states in the absence of insulin. The mechanism involves IRS-1 phosphorylation by AMPK and enhanced binding of rictor and TSC1 to PI3K.
This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
Abstract 3952: Late Outgrowth Endothelial Progenitor Cells From Patients With AMI Improve Left Ventricular Ejection Fraction In Experimental Myocardial Infarction
Authors: Knoedler Martina , Weidl Eliane , Gawehn Sandra , Schurmann Maren , Stein Andreas , Seidl Stefan , Peschel Christian , Oostendorp Robert , Ott Ilka 
Published: July 2021

Background: Recent studies suggest that endothelial progenitor cells (EPC) from bone marrow or peripheral blood improve myocardial function in experimental myocardial infarction (MI). Since applications for cell therapy are limited by the number of available cells, expansion of EPC may facilitate its therapeutic use in ischemic disease. The aim of this study was to expand late outgrowth EPC from peripheral blood from patients with acute myocardial infarction, characterize them and investigate their therapeutic effect in experimental MI.
Methods and Results: Venous blood samples were obtained from patients with acute MI (n=51), stable angina (sAP, n=57) and healthy controls (H,n=47). CD34+ cells were isolated using immunomagnetic beads (Miltenyi Biotec). CD34+ cells cultured on fibronectin in endothelial cell medium formed colonies after 1–2 weeks and were further expanded for up to 3 months to generate late outgrowth EPC (eEPC). Expansion was observed up to 2.9x10′9 (MI), 11x10′9 (sAP) and 7x10′9 cells (H) with a mean culture duration of 61 days. Expanded cells showed an endothelial morphology and expressed endothelial surface markers (CD31, VEGF-R2, CD105). Intramyocardial transplantion of 1x10′6 eEPC in experimental myocardial infarction in athymic nude rats revealed improvement in echocardiographic ejection fraction after 2 weeks. This was associated with enhanced vessel density after 1 week and increased mRNA expression of HGF. No differences in infarct size were observed. Similarly in a chronic model of myocardial infarction (eEPC transplantation 1 week after MI) myocardial function significantly improved after 5 weeks in comparison to the control group.
Conclusion: Expansion of eEPC from circulating CD34+ cells in patients with coronary artery disease is feasible and improves myocardial function after local transplantation in acute and chronic myocardial infarction. The large number of generated eEPC may prove benefical for therapeutic use and this advantage may prevail time-consuming expansion procedures.
Abstract 5261: Platelet-Depletion Ameliorates Cardiac Function and Disease Severity in Experimental Autoimmune Myocarditis
Authors: Russ Martin , Seliger Barbara , Hauptmann Steffen , Marty Rene , Bukur Jürgen , Eriksson Urs , Schubert Sebastian , Werdan Karl , Buerke Michael 
Published: July 2021

Introduction: Experimental Autoimmune Myocarditis (EAM) is a CD4+ T cell mediated model of inflammatory cardiomyopathy. Activated platelets express CD154, a molecule critical to adaptive immune responses, which has been implicated in platelet-mediated modulation of inflammation.
Hypothesis: Platelets are critical for the generation of heart-specific, autoreactive T-cell responses in a model of experimental Autoimmune Myocarditis.
Methods: BALB/c mice were immunized twice at day 0 and day 7 with 100μg alpha-MyHC-peptide (614–29) together with Complete Freund‘s adjuvant. Platelets were markedly depleted by i.v. injection of a GP1alpha antibody every 5th day (n=8). Control mice were injected with a non-depleting isotype antibody (n=8). Mice were assessed at day 28 for heart dimensions and cardiac function using echocardiography. After lethal anesthesia, hearts were removed and analyzed for heart weight/body weight ratio and histological severity scores. CD4+ T-cells were isolated from spleens, and analyzed for CD154 and IL-17 expression using FACS after in vitro re-stimulation on alpha-MyHC pulsed, irradiated antigen presenting cells.

Results: Modest platelet depletion protected from left ventricular dilatation, and preserved left ventricular ejection fraction in immunized mice. Myocarditis prevalence and severity scores were significantly reduced in depleted animals. Relative numbers of spleen-derived CD4+ T-cells expressing CD154 or IL-17, were significantly reduced in the treatment group (table

).

Conclusion: Our findings suggest that platelets might play a critical role in the development of heart-specific autoimmunity and cardiomyopathy. Further studies are needed to confirm these findings, which suggest a novel treatment approach for inflammatory cardiomyopathy.

Echocardiography - Histology - FACS
Abstract 5341: Spatial Heterogeneity Of The Mitochondrial Membrane Potential Underlying Arrhythmias In Pressure Overload Hypertrophy
Authors: Jin Hongwei , Chemaly Elie R , Lyon Alex , Stocks Joanne , Akar Fadi G 
Published: July 2021

Increased production and/or impaired scavenging of reactive oxygen species (ROS) are a hallmark of mitochondrial dysfunction in structural heart disease. Previously, we demonstrated a mechanism by which depolarization of the mitochondrial membrane potential (mitoVm) caused by ROS release through the mitochondrial benzodiazepine receptor (mBZR) promotes conduction failure. Since pressure overload hypertrophy (PoH) is a major risk factor for sudden death, we hypothesized that instability of mitoVm in PoH predisposes to arrhythmias.
Methods: PoH was produced in rats by ascending aortic banding for 4 weeks. LV dysfunction characteristic of PoH was confirmed in vivo using M mode 2D echocardiography. Ultrahigh resolution optical imaging was performed in ex vivo perfused hearts from PoH (n=6) and normal (n=3) rats. Normalized mitoVm was measured using a novel quantitative technique of TMRM imaging with subcellular resolution during a protocol of ischemia (for 7min) and reperfusion. Mean and SD mitoVm across 6400 sites were compared as was the expression of the mBZR gene (PKBS) using western blot analysis.
Results: Aortic banding for 4 weeks resulted in a significant increase in LV anteroseptal and posterior wall dimensions consistent with structural remodeling in PoH. Ischemia reperfusion related ventricular fibrillation (VF) was observed in 5/6 PoH and 1/3 normal hearts. Average mitoVm was surprisingly greater in PoH compared to normal hearts during both ischemia (17%, p=0.012) and reperfusion (24%, p=0.004). However, spatial heterogeneity of mitoVm indexed by SD was markedly greater in PoH during ischemia (0.42 vs 0.11, p=0.00007) but not reperfusion (p=0.15). Analysis of mitoVm in susceptible (VF+) versus resistant (VF−) rats revealed a 4X increase in mitoVm heterogeneity in ischemia (p=0.0004) but not reperfusion (p=0.12) in the VF+ group. There were no differences in overall protein content of PKBS between groups indicating that altered mitoVm dynamics are independent of PKBS expression.
Conclusions: These data demonstrate that increased spatial heterogeneity of mitoVm during ischemia in PoH promotes VF. Strategies aimed at preventing the desynchronization of mitoVm may form a novel therapeutic approach for combating malignant arrhythmias.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 5519: High Resolution Genetic Mapping Strategies for Metabolic Disease in Mice: Towards Association Based Studies
Authors: Bennett Brian J , Farber Charles R , Orozco Luz , Lusis Aldons J 
Published: July 2021

Background: Common complex diseases, such as atherosclerosis, diabetes and obesity, are the result of genetic, environmental and gene/environmental interactions. Genetic studies using mice have relied on linkage studies where two mouse strains with different disease phenotypes are crossed to identify a genetic loci conferring susceptibility or resistance to the disease. One limitation with such an approach is that linkage areas are many megabases in size and thus gene resolution is low. Recently, several whole genome association studies in large human cohorts have reported single nucleotide polymorphisms (SNPs) associated with common forms of disease. We have begun similar association based approaches to common diseases using mice. One important advantage of murine association studies is that association results can be validated biologically with knockout or transgenic approaches.
Methods and Results: Our initial studies have focused on the metabolic syndrome and we have collected traits related to diabetes, adiposity and cholesterol metabolism. We have phenotyped 100 strains of mice including a panel of classic inbred mice and several panels of recombinant inbred mice (BxH, AxB, BxA and BxD). We report here our initial strategy for association in mice, power calculations and describe strain selection along with initial phenotypes and associations. Our laboratory has previously identified linkage peaks on chromosome 1 for HDL and Total Cholesterol. Studies from our laboratory and others have identified apolipoprotein A2 as a major determinate of circulating lipoproteins in mice. As a proof of principle we have focused on associations of total cholesterol and HDL cholesterol at the A2 locus on chromosome 1 and demonstrate the increased resolution of this approach. We also report loci contributing to HDL and total cholesterol levels from independent F2 crosses and coincident lipoprotein associations in the mouse diversity panel.
Conclusion: Association based studies in mice have high resolution can successfully identify previously validated genes. Studies are currently ongoing to validate novel SNPs associated with other metabolic phenotypes.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 568: Coronary Artery Plaque Spatial Distribution Matches that of Thrombosis in STEMI, and is Underestimated by Calcified Plaque Segments Alone
Authors: Pastorius Catherine A , Merkel-Kraus Stacia , Schwartz Jonathan G , Schwartz Robert S , Pink Vicki , Peichel Gretchen , Lesser John R , Knickelbine Thomas , Flygenring Bjorn , Longe Terry , Duval sue 
Published: July 2021

Angiographic studies of ST-elevation myocardial infarction (STEMI) show that occlusive thrombi occur in coronary arteries within the proximal third of each major vessel, within about 35 mm from the ostium. These findings suggest that these high-risk regions are sites of plaque vulnerability. Multidetector CTA (MDCTA) visualizes not only lumen but also calcified and uncalcified coronary plaque. We therefore studied the distribution of coronary plaque in patients to determine plaque distribution to compare result with location of angiographic myocardial infarction thrombus.
Methods: 48 outpatients (mean age 57 +− 5) undergoing Dual Source MDCTA (asymptomatic or with atypical symptoms) were studied. Most distal plaque location was measured for ostial-termination distance and composition (calcified/noncalcified) determined by one expert observer using validated, commercial plaque characterization software for lesion location and lesion length.
Results: Location of the most distal plaque was as follows, LAD (n=35) 31.8 mm, LCX (n=21) 33.0 mm, and RCA (n=24) 56.0 mm. Mean lesion lengths were LAD 19.4 +− 13.4 mm, LCX 15.1 +− 9.6 and RCA 18.4 +− 9.8 mm. Mean volume (cu mm) for calcified and noncalcified plaque was 130 +− 176 and 204 +− 249 respectively, for a ratio of 0.64. There was no propensity of either calcified or uncalcified plaque to aggregate longitudinally in the arteries.
Conclusions:

The distribution and location of coronary artery plaque by MDCTA identically matches the known location of coronary artery vulnerability determined by angiographic studies. This finding suggests that STEMI does not occur in distal coronary locations simply because little plaque occurs in these areas.

Calcified plaque volume measured in 3-dimensions underestimates total plaque volume by a factor of 2.6. Calcific plaque is thus the ‘tip of the iceberg’.
Abstract 596: Therapeutic Hypothermia After Cardiac Arrest: A Cost-Effectiveness Analysis
Authors: Mader Timothy J , Bowdoin Jennifer J , Nobles Carrie J 
Published: July 2021

Background: Mild induced therapeutic hypothermia (TH) is currently recommended for survivors of out-of-hospital cardiac arrest (OHCA) who meet specified criteria. If TH were fully implemented in the US, 2298 additional OHCA victims every year could be expected to survive. Despite a 2006 meta-analysis clearly demonstrating a decrease in mortality and an improvement in neurological outcome (with no treatment-limiting side effects) for TH, clinicians have been reluctant to adopt the therapy, often citing cost as a reason. The aim of this study was to determine the cost-effectiveness (CE) of TH after OHCA relative to supportive care.
Methods: Monte Carlo simulation was used to approximate the cost per in-hospital death prevented, the cost per poor neurological outcome averted, and annual hospital costs. Estimates of effectiveness and resource use were extracted from secondary data sources. Included variables were: in-hospital mortality, neurological status, ICU and hospital ward length-of-stay (LOS), ICU and hospital ward cost/day, equipment costs, physician time, and medications. For our base case, we calculated the CE of treating 60 patients/year using a moderate cost method. We did sensitivity analyses through systematic bidirectional adjustments of selected variables’ costs, by reducing the treated patients/year to 12, and by excluding the cost of medications and physician time. All analyses were done from a US hospital perspective and reported in 2008 US$.
Results: LOS dominated the difference in cost. The median cost per death prevented was $280,092 [IQR $202,279-$386,215] and per poor neurological outcome averted it was $147,314 [IQR $118,009-$182,251]. The median annual cost to treat 60 patients/year using a moderate cost method was $1,588,730 [IQR $1,322,343-$1,865,462]. Reducing the number of patients treated per year to 12 lowered the annual cost to $319,759 [IQR $268,122-$373,670]. The results of all other sensitivity analyses were similar to the base case. Assuming a mean duration of survival following hospital discharge of 6.13 years, TH had a cost/life-year saved of $45,692, which compares favorably to other life-saving health and social interventions.
Conclusion: TH after OHCA is a relatively cost-effective treatment modality.