bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1805: Chromosome 9p21.3 Genetic Variation is Associated with Angiographic CAD but not with CAD Disease Burden
Authors: Mower Chrissa P , Anderson Jeffrey L , Horne Benjamin D , Park James J , Coleman Jesse L , May Heidi T , Jahromi Mona S , Carlquist John F 
Published: July 2021

Genetic variation at the 9p21.3 locus rs2383206 is associated with coronary heart disease (CHD) phenotypes. In a comparison of patients with and without angiographically confirmed CHD, the G allele of rs2383206 was present more frequently in diseased vs controls (normal angiograms). However, the pathophysiologic impact, whether it affects initiation, severity, or triggers an event, of the 9p21.3 locus remains unknown. We sought to determine whether 9p21.3 variation affects disease severity (promotion) by assessing its association with CAD burden.
Methods: Genotyping for rs2383206 using 5′exonuclease chemistry (Taqman) was performed on 1759 subjects. Subjects were grouped as homozygous wild-type (low risk), heterozygous (intermediate risk) or homozygous risk-associated genotype (high risk). Disease burden was assessed by 1, 2, or 3 vessels; ≥70% stenosis and the validated Duke CAD Index (DCI). Comparison used a chi-square test (single vs multivessel disease) and analysis of variance (ANOVA) for the DCI comparison.
Results: Average age 51.1± 7.4 years, 64.0% male. Frequency of the CAD risk allele did not differ among groups with 1, 2, or 3 vessel disease. There was no difference among groups with respect to the DCI. After adjustment for standard cardiac risk factors, the rs2383206 genotype was associated with CAD compared to controls (OR (CI)=1.73(1.26–1.85), p=0.001).
Conclusion: The rs2383206 polymorphism was not associated with CAD disease burden. Findings suggest the rs2383206 polymorphism, although associated with disease onset is not likely involved in its progression. These findings will aid in refining the application of 9p21.3 for risk assessment and developing novel preventive and therapeutic strategies.
Abstract 1941: The Anti Von Willebrand Factor Aptamer ARC1779 Effectively Inhibits Platelet Activation and Adhesion
Authors: Duerschmied Daniel , Wagner Patricia , Gilbert Madaline , Gilbert James , Wagner Denisa , Schaub Robert 
Published: July 2021

Objectives Immediately after vessel wall damage, plasma von Willebrand factor (VWF) binds to exposed collagen and laminin, enabling the subsequent adhesion of platelets to immobilized VWF via glycoprotein (GP) Ibα. The GPIbα-VWF interaction is able to withstand high (arterial and intrastenotic) shear conditions, rendering this mechanism crucial for the initiation of hemostatic and thrombotic processes in the arterial circulation. In addition, released VWF promotes platelet activation. We have generated a nuclease-resistant anti-VWF A1 domain aptamer, ARC1779. Aptamers are nucleic acid molecules with high affinity and specificity due to the ability to fold into unique three dimensional structures. We examined the ability of ARC1779 to inhibit these platelet activation processes.
Methods and Results Botrocetin-induced aggregation of platelet-rich plasma (IC90 ~100–300 nM) and shear force-induced platelet aggregation in whole blood (IC95 ~100 nM) were inhibited by ARC1779. Platelet adhesion was assessed under high shear conditions (1500/s) in a parallel plate flow chamber using calcein orange labeled platelets. ARC1779 at a concentration range of 7.5 nM − 375 nM produced a concentration dependent inhibition of platelet adhesion with an IC50 of 7.5 nM and IC90 of 75 nM. Almost complete abolition of platelet adhesion was achieved with 400 nM of the aptamer. Firm adhesion of platelets was assessed by monitoring time of adhesion of randomly selected adherent platelets treated with 200 nM of ARC1779. The time that ARC1779 treated platelets remained attached was significantly reduced compared to untreated platelets (p<0.001). The occlusion time after electrical injury of carotid arteries in cynomolgus macaques was assessed and found to be significantly prolonged during ARC1779 treatment. At a concentration of 700 nM, ARC1779 inhibited occlusion of the injured carotid arteries as effectively as the GPIIb/IIIa antagonist abciximab at 1300 nM. The bleeding time was significantly shorter with ARC1779 than with abciximab.
Conclusions ARC1779 constitutes a promising novel anti-platelet agent for various thrombotic indications.
Abstract 3390: Impairment of Post-ischemic Neovascularization in Mice Lacking IQGAP1, an Actin-binding Scaffold Protein: Role in Macrophage Infiltration and ROS production
Authors: Urao Norifumi , McKinney Ronald , Fukai Tohru , Ushio-Fukai Masuko 
Published: July 2021

Neovascularization is important repair mechanism in response to ischemic injury and its process is in part dependent on reactive oxygen species (ROS). IQGAP1, an actin-binding scaffold protein, is key regulator for actin cytoskeleton and motility. We demonstrated that IQGAP1 is expressed in endothelial cells (ECs) and mediates VEGF-induced ROS production and migration of cultured ECs. However, its role in postnatal neovascularization is unknown. Here we show that neovascularization induced by hindlimb ischemia is significantly inhibited in IQGAP1-deficient mice as evaluated by laser Doppler blood flow (38%), capillary density (48%) and alpha-actin positive arterioles (68%). In wild-type (WT) mice, western and immunofluorescence analysis reveal that IQGAP1 protein expression in ischemic tissues is significantly increased at Mac3+ macrophages and lectin+ capillary-like ECs at 3 days and 7 days after ischemia, respectively, which is associated with increased superoxide production. Of note, macrophage infiltration is important for post-ischemic revascularization. Mice lacking IQGAP1 show significant decrease in the number of infiltrated Mac3-positive macrophage and superoxide production in ischemic muscles (30% and 52%, respectively) as compared to WT mice. Numbers of inflammatory cells and cKit+/Flk1+ endothelial progenitor cells in peripheral blood are not affected in these knockout mice. Moreover, thioglycollate-induced peritoneal leukocyte recruitment and accumulation are significantly inhibited in IQGAP1-deficient mice (53%), whereas white blood cell number is not changed. In vitro, peritonitis-elicited (activated) macrophages obtained from IQGAP1-deficient mice show impaired polarization of actin, as visualized by phalloidin staining as well as complete inhibition of migration towards stromal derived factor-1 and VEGF, as measured by modified Boyden-chambered method. In summary, IQGAP1 plays a key role in reparative neovascularization in response to tissue ischemia by regulating not only ECs but also macrophage migration/infiltration as well as ROS production in the vessel growth area. Thus, IQGAP1 is a potential therapeutic target to promote neovascularization in ischemic cardiovascular diseases.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 3689: Loss of Myeloid Related Protein-8/14 Exacerbates Cardiac Allograft Rejection
Authors: Shimizu Koichi , Libby Peter , Rocha Viviane Z , Folco Eduardo J , Shubiki Rica , Croce Kevin J , Hogg Nancy , Mitchell Richard N , Simon Daniel I 
Published: July 2021

Background: The S100 calcium-binding proteins MRP-8 (S100A8) and MRP-14 (S100A9) heterodimerize to form MRP-8/14 complexes that regulate myeloid cell function, control inflammatory responses, and serve as an early serum marker for monitoring acute allograft rejection. Despite functioning as a putative pro-inflammatory mediator, the pathophysiological role of MRP-8/14 in cardiovascular disease remains unknown. This study used murine cardiac transplantation to investigate the role of MRP-14 in cardiac allograft rejection using MRP-14-deficient mice (MRP14−/−) lacking MRP-8/14 complexes.
Results: In major histocompatibility complex class II allomismatched cardiac transplantation (bm12 donor hearts and C57BL/6 recipients), allograft survival averaged 5.9 ± 2.9 weeks (n=10) in MRP14−/ −recipients compared to > 12 weeks (n = 15, p<0.0001) in wild-type (WT) recipients. At 2 week post-transplantation, allografts in MRP14−/ − recipients had significantly higher parenchymal rejection (PR) scores (2.8 ± 0.8, n=8) than WT recipients (0.8 ± 0.8, n=12, p<0.0001). MRP14−/ − recipients had significantly increased allograft accumulation of T cells and macrophages and mRNA levels of IFN-γ and IFN-γ–associated chemokines (IP-10, Mig, and I-TAC) compared to WT recipients. The MRP14−/− recipients also had significantly more lymphocytes in draining lymph nodes than WT recipients (cell number per lymph nodes: 23.7 ± 0.7 x 105 for MRP14−/− vs. 6.0 ± 0.2 x 105 for WT, p < 0.0001). MRP14−/− dendritic cells (DC) stimulated with IFN-γ expressed significantly higher levels of the co-stimulatory molecules CD86 and ICOSL, and mixed leukocyte reaction using allo-EC-primed MRP14−/− DC resulted in significantly higher antigen-presenting function than WT DC.
Conclusion: Taken together, these observations indicate that MRP-8/14 complexes participate in acute allograft rejection by modulating dendritic cell antigen presentation and T cell priming. The unexpected finding that deficiency of MRP-8/14 complexes exacerbates acute allograft rejection indicates that MRP-8/14 has distinct roles in modulating immune cell functions, such as migration and antigen presentation.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 3719: Deletion of Angiotensin II type 2 Receptor Accelerates Adipogenesis in Murine Mesenchymal Stem Cells with Wnt 10b/beta-catenin Signaling: Potential Link to Obesity and Metabolic Syndrome
Authors: Matsushita Kenichi , Wu Yaojiong , Wang Hao , Pratt Richard E , Dzau Victor J 
Published: July 2021

Recent evidence suggests that the reninangiotensin system (RAS) plays a vital role in adipocyte biology and the pathophysiology of metabolic syndrome. Obesity is a major risk factor and mesenchymal stem cells (MSCs) are suggested to be an important source of new fat cells. Previously we reported that MSCs have all the components of the RAS and that angiotensin II (Ang II) can influence adipocyte differentiation. However, the effect of Ang II type 2 receptor (AT2R) deletion on adipogenesis in mouse model is unknown. Accordingly, we employed AT2R-null mice and examined the role of AT2R in the differentiation of MSCs to adipocytes.
Methods and Results: Murine MSCs were isolated from AT2R-null mice and wildtype littermates (WT). Confluent MSCs were differentiated into adipocytes by the established protocol. Adipogenesis was quantitated by assessing lipid droplet accumulation using 2 different methods. Using the fluorescent dye which binds to lipid droplets (AdipoRed), AT2R-null group showed significantly increased total fluorescence (261.6 ± 49.6 % vs. WT) on day 7. Oil red O staining, followed by extraction of the absorbed dye and measurement of the absorbance on day 14, also exhibited that AT2R-null group showed significantly increased lipid droplet accumulation (202.7 ± 14.1 % vs. WT). We next examined the expression of adipocyte-specific genes by real-time RT-PCR. AT2R-null group exhibited a significantly increased expression of PPARγ, fatty acid synthase, and adiponectin (vs. WT). Since Wnt 10b/beta-catenin signaling is reported to play an important role to inhibit adipogenesis, we further examined it by real-time RT-PCR and immunoblotting. The AT2R-null group exhibited significantly decreased Wnt 10b expression accompanied by a decrease of cellular beta-catenin (vs. WT).
Conclusion: Our results demonstrate that the AT2 receptor has an inhibitory effect on adipogenic differentiation in murine mesenchymal stem cells. Moreover, this inhibitory effect is associated with Wnt 10b/beta-catenin signaling which plays an important role to inhibit adipogenesis. These results provide important insights into the pathophysiology of obesity and obesity related consequences such as metabolic syndrome and may identify potential therapeutic targets.
Abstract 3774: A Novel Protein Phosphatase in SR Calcium and Cardiac Contractile Regulation
Authors: Ruan Hongmei , Lu Gang , Wang Yibin 
Published: July 2021

Loss of contractility is a common feature in heart failure. Sarcoplasmic Reticulum (SR) calcium cycling defect is a major mechanism underlying contractile dysfunction. Phospholamban (PLB) mediated regulation of SERCA activity in normal and failing heart plays an important role in SR calcium cycling. Recently, we discovered a novel isoform of protein phosphatase 2C family (PP2Ce) which is specifically targeted on ER membrane. Northern-blot showed that PP2Ce is highly expressed in heart and other tissue. Expression of PP2Ce in neonatal cardiomyocytes significantly repressed the PLB phosphorylation at the Thr-17 site without remarkable effect on Ser-16 site, which indicating its potent and very specific activity towards the Thr-17 site instead of the Ser-16 site of PLB in cardiomyocytes. By using an inducible a-MHC-in-PP2Ce construct and the Tet-expresser transgenic line, we developed a cardiac specific PP2Ce transgenic mice. PP2Ce expression was remarkably higher in transgenic hearts compared with control, accompanying with the increase in expression of phosphor-CaMKII. There were no significant difference in the cardiac function at basal based on Echocardiography measurements. Expression of PP2Ce markedly delayed the decay of calcium transients with the administration isoproterenol in isolated adult cardiomyocytes and blunted positive inotropic response in transgenic mice heart. In response to ISO treatment, PLB phosphorylation at the Thr-17 site were significantly suppressed in PP2Ce cardaiomyocytes and hearts, while there is no much change at Ser-16 site compared with controls. Our results suggested that PP2Ce may be a novel component of the PLB/SR calcium regulatory machinery involved in cardiac contractile regulation under physiological and pathological conditions and offer new insights to cardiac contractile regulation and failure.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 5372: In Vivo Myocardial Distribution of Adult Stem Cells Immediately Following Intracoronary Delivery in a Swine Model of Myocardial Infarction
Authors: Ly Hung , Hoshino Kozo , Pomerantseva Irina , Kawase Yoshiaki , Yoneyama Ryuichi , Takewa Yoshiaki , Vooght Carrie , Frangioni John V , Hajjar Roger J 
Published: July 2021

Background: Cardiac cell-based therapy (CCT) has emerged as a promising therapeutic strategy. There are few data comparing the fate of different stem cell (SC) populations delivered by the intracoronary injection (ICI).
Aim: Document the in vivo myocardial distribution of SC delivered by ICI following recent myocardial infarction.
Methods: In a myocardial infarction swine model, near-infrared (NIR) fluorescence was used to provide high sensitivity in vivo tracking of SC in the immediate phase (< 60 minutes) after ICI of 2x107 cells. After labeling with the NIR fluorophore, IR-786, the NIR signal intensities and myocardial distribution patterns of mesenchymal (MSC), bone marrow-(BMMNC) and peripheral blood-mononuclear (PBMNC) cells were compared using an open-chested fluorescence imaging system.

Results: The SC populations of interest were successfully loaded with IR-786. While all SC populations readily distributed along the vascular territory of the infarct-related artery immediately after injection, there was a mean SI intensity drop of 29.8% and 14.1% for PBMNC and BMNC (p<0.05), respectively, which correlated with poor cell retention. No significant SI change was found in MSC-injected swine, which was associated with less cell loss after delivery. There was also evidence of MSC-related vessel plugging in some swine (Figure

).

Conclusion: Our in vivo findings suggest that immediately after injection (during the first 60min ICI), there is already evidence of poor SC retention and distribution vary depending on cell population, potentially impacting clinical efficacy and safety of CCT.
Abstract 5394: H11 Kinase/Hsp22, A Novel Mechanism in the Transition to Heart Failure
Authors: Qiu Hongyu , Hong Chull , Gao Shumin , Vatner Dorothy E , Vatner Stephen F , Depre Christophe 
Published: July 2021

H11 kinase/Hsp22 (H11K), a heat shock protein expressed mainly in the heart, is up-regulated upon pressure overload in animal models and in patients. Cardiac-specific over-expression of H11K in a transgenic model induces cardiac hypertrophy with normal function and cardioprotection against lethal ischemia. We tested the hypothesis that H11K deletion would accelerate the transition into heart failure (HF) following chronic pressure overload. An H11K knockout (KO) mouse was generated, which survives after birth with normal Mendelian distribution. In basal conditions (4/group), no differences were found between KO and wild type (WT) in terms of left ventricular (LV) mass (LV/tibial length: 4.6±0.3 vs 4.1±0.1, NS) or LV ejection fraction (69±3% vs 70±1%, NS). After two weeks aortic banding the KO mice, compared to WT, showed a slightly greater mass (LV/tibial length: 8.2±0.3 vs 7.0±0.4, P<0.05), impaired LV function (LV ejection fraction: 45±3% vs 62±5%, P<0.05), and signs of HF (lung weight/TL: 16.2±3 vs 7.7±0.4, P<0.05; LV end-diastolic pressure: 22±4 mmHg vs 7±4 mmHg, P<0.05). To test whether H11K participates in cardiac cell survival, both WT and KO mice were submitted to 30 min no-flow ischemia of the left anterior descending artery followed by 24 hours reperfusion and staining for the area-at-risk (AAR) and infarct size (IS). Whereas AAR was comparable between groups, the IS/AAR was more than doubled (P<0.01, n=3/group) in KO (61±2.8%) compared to WT (26±2.8%). Therefore, H11K deletion does not affect basal cardiac function but it precipitates the transition into HF following pressure overload, potentially by loss of H11K cardioprotective action.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 571: Prognostic Value of Albuminuria on One Month Mortality in Acute Myocardial Infarction
Authors: Schiele Francois , Meneveau Nicolas , Chopard Romain , Descotes-Genon Vincent , Oettinger Joanna , Seronde Marie-France , Ecarnot Fiona , Bassand Jean-Pierre 
Published: July 2021

Background: Albuminuria is associated with hypertension, renal and endothelial dysfunction, inflammation, insulin resistance and atherogenic lipid profile. An increase in albuminuria occurs in the early days after acute myocardial infarction. The aim of this study was to assess the relation between albuminuria and 30 day mortality, as well as its incremental predictive value on top of established prognostic parameters.
Methods: Demographic, clinical and biological characteristics at admission, in-hospital treatments and one month survival were recorded in 1188 consecutive patients admitted for acute myocardial infarction. Albuminuria was assessed from an 8-hour, overnight urine collection at day 3 using immunonephelemetry. The population was categorized according to albuminuria <20, 20 to 200 and >200 μg/min.
Results: Fifty one percent (625/1188) of patients had an albuminuria level below 20 μg/min, 40% (296) between 20 and 200 μg/min and 9% (109) above 200 μg/min. High levels of albuminuria were associated with older age, history of hypertension, previous surgical coronary revascularization, stroke or peripheral vessel disease. Albuminuria was also correlated with troponin release, BNP and high sensitive CRP. At one month, there was a significantly higher mortality rate in groups with higher albuminuria (31/635(5%), 64/477(13%) and 22/109(20%) for albuminuria <20, 20–200 and >200 μg/min respectively). Multivariable analysis showed that albuminuria was an independent predictor of mortality. After adjustment on the GRACE risk score and the use of guidelines-recommended treatments, patients with albuminuria >20 μl/min had a 4-fold higher 30 day mortality, and those >200 μl/min had a 5 fold higher 30 day mortality, as compared with patients with albuminuria <20 μl/min (OR 4 [1.3–12.5] and 5.9 [1.64–20] for albuminuria >20 μl/min and >200 μl/min respectively).
Conclusions: Albuminuria level is an independent and powerful predictor of mortality after acute myocardial infarction.
Abstract 705: The Difference in Left Ventricular Twisting Behavior Between Patients With Hypertensive Heart Disease and Hypertrophic Cardiomyopathy
Authors: Nishimura Kazuhisa , Okayama Hideki , Saito Makoto , Inoue Katsuji , Yoshii Toyofumi , Hiasa Go , Sumimoto Takumi , Suzuki Jun , Ogimoto Akiyoshi , Ohtsuka Tomoaki , Funada Junichi , Higaki jitsuo 
Published: July 2021

(Background) Left ventricular (LV) untwisting behavior is a novel index of LV diastolic function since it is a powerful determinant of LV diastolic suction. The LV of patients with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) has diastolic dysfunction despite normal systolic function. However, the role of untwisting behavior in HCM and HHD in the pathophysiology of diastolic dysfunction is unknown. The aim of this study was to investigate the difference of LV twisting behavior between patients with HCM and HHD.
(Methods) Forty-four patients with HCM (mean age, 63+/−15 y, 34 males), 30 patients with HHD (mean age, 62+/−12 y, 20 males), and 20 age and sex-matched control subjects were evaluated. After a standard echocardiographic examination, LV twist and twisting velocity profiles from apical and basal short-axis images were analyzed using two-dimensional speckle tracking imaging. All temporal parameters were normalized by R-R intervals.

(Results) LV diastolic and systolic dimensions, and ejection fraction were not significantly different among the groups. LV mass index and early diastolic mitral annular velocity were not significantly different between the HCM and HHD groups. The peak torsion in the HCM and HHD groups was significantly greater than that in the control group (Table

). The peak untwisting velocity in the HCM group was comparable to that in the control group. However, when the peak untwisting velocity was corrected by peak torsion, the value in the HCM group was significantly decreased compared with that in the HHD and control groups. The time to peak untwisting velocity from aortic valve closure in the HCM group was significantly longer than that in the HHD and control groups.

(Conclusion) These results suggest that enhanced peak torsion in HCM might compensate for untwisting behavior, but this mechanism fails to fully compensate for untwisting behavior compared with HHD.

Left ventricular twisting behavior