bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 394: Murine Cre/flox Studies Indicate Yolk Sac Derived Macrophages Are the Cellular Source of FXIIIA
Authors: Beckers Cora M , Griffin Kathryn J , Simpson Kingsley J , Brown Jane M , Cordell Paul A , Smith Kerrie A , Drinkhill Mark J , Kearney Mark T , Vacher Jean J , Pease Richard J , Grant Peter J 
Published: March 2022

Fibrin clot cross-linking FXIIIA has a plasma and cellular pool. It is present in platelets, macrophages and connective tissues. However, it is unknown how FXIIIA is secreted and which cell type maintains the plasma pool, although the platelet is considered the main candidate. To address this we have induced lineage specific deletion in mice floxed in coding exon 7 of the FXIIIA gene. Mice homozygous for the floxed gene and transgenic for Pf4cre-recombinase (thrombopoietic deletion), CD11bcre or LysMcre (myeloid deletions) were generated. A FXIIIA KO was obtained using a CMV-driven cre. Plasma and platelet FXIIIA protein & activity and FXIIIA mRNA in brain, heart and aorta were determined and compared to WT, FXIIIA floxed and thrombocytopenic Mpl (thrombopoietin receptor) KO mice.
FXIIIA KO and Pf4FXIIIA KO mice lack platelet FXIIIA protein & activity, whereas both are normal in the Mpl KO. pFXIIIA is absent in the FXIIIA KO and decreased in Pf4FXIIIA KO (by 85%), CD11bFXIIIA KO (40%) and LysMFXIIIA KO (60%) whereas in WT, FXIIIA floxed and Mpl KO pFXIIIA was unaltered. Mpl KO platelet size as determined by FACS was also unaltered. These data confirm that platelets are not the source of pFXIIIA. These data also demonstrate that the pFXIIIA secreting cells are Pf4 dependent & Mpl independent: a combination not seen in BM-derived cells. Thus, we are looking for a macrophage-like cell outside of the BM.
Resident macrophages in the brain are yolk sac-derived and uniquely, not replaced from BM under normal conditions. In young uninjured brain FXIIIA mRNA levels were knocked down by 96.8% in Pf4FXIIIA KO and by 37.8% in the Mpl KO, confirming, for the first time, the existence of a Pf4 dependent Mpl independent cell from the yolk sac.
In heart cell fractions, the smallest Thy1+ fraction (3% of total) contained the largest FXIII-A mRNA pool, which decreases in Pf4cre & CD11bcre-Flox mice, further supporting involvement of yolk sac-derived macrophages.
Further study of FXIIIA mRNA expression in Pf4 dependent, Mpl independent cells in the cardiovascular system demonstrated that the pFXIIIA profile was most closely mirrored by the reduction in arterial wall FXIIIA mRNA suggesting that yolk sac derived arterial wall resident macrophages are the cellular source of FXIIIA.
Abstract 398: Inhibition of Tissue Factor Reduces Thrombosis and Inflammation Without Increased Bleeding in a Mouse Model of Ischemic Stroke
Authors: Wang Shaobin , Reeves Brandi , Kirchhofer Daniel , Pawlinski Rafal 
Published: March 2022

Tissue factor (TF), the primary initiator of the extrinsic coagulation cascade, is highly expressed by astrocytes surrounding blood vessels in the central nervous system. Using mouse models of hemorrhagic and ischemic stroke, we previously demonstrated that astrocyte TF plays a critical role in brain hemostasis while also contributing to neuronal damage. Importantly, using mice with different levels of astrocyte TF expression, we determined that an astrocyte TF activity around 5% of the wild type level was sufficient to limit bleeding in hemorrhagic stroke and at the same time was low enough to reduce infarct size and behavioral deficits in ischemic stroke, without increased hemorrhagic transformation. Therefore, we hypothesized that pharmacologic inhibition of TF may improve outcomes after ischemic stroke and have a wide safety margin.
To test this hypothesis, C56Bl/6J mice were subjected to middle cerebral artery occlusion (MCAO) for 1 hour followed by 24 hours of reperfusion. Inhibitory rat anti- mouse TF antibody (1H1) and control IgG were administered as a bolus intraperitoneal injection immediately after ischemia. Inhibition of TF dose-dependently reduced brain infarct size in female mice (36.6±1.4% of total brain volume in IgG group [n=19] vs 28.3 ± 1.7% in 25mg/kg 1H1 group [n=9, p<0.01] and 18.5 ±2.3% in 75mg/kg 1H1 group [n=8, p<0.001]; mean±SEM). Importantly, 1H1 did not exacerbate hemorrhagic transformation during the reperfusion phase. Furthermore, TF inhibition significantly reduced microvascular thrombosis (analyzed by fibrin staining), expression of inflammatory markers in the injured brain (IL-6, MCP-1 and KC levels- analyzed by ELISA) and attenuated behavioral deficit after ischemic stroke. Subjecting male mice to the same MCAO condition resulted in partial lethality in IgG treated group (4 out of 6 mice died with 24 hours) which was prevented by 1H1 (25mg/kg) treatment (0 out of 5, Log-rank test p=0.031).
Altogether, our data suggest that the overabundance of astrocyte TF expression resulted from selective pressure to limit intracerebral hemorrhage after traumatic brain injury, but in the modern era poses the additional risk of increased injury during ischemic stroke.
Abstract 493: Syndesomes: An Syndecan-4 Based Therapeutic for Effective Revascularization in Peripheral Ischemia in Diabetes
Authors: Das Subhamoy , Singh Gunjan , Monteforte Anthony J , Martinez Matthew E , Wright Catherine S , Martin Patricia E , Dunn Andrew K , Baker Aaron B 
Published: March 2022

Previous research has attempted to use growth factor proteins and genes to revascularize ischemic tissues but none of the methods have found complete success in clinical trials. We have demonstrated the loss of co-receptors like syndecan-4 due to long-term diseased state and enhanced neovascularization of ischemic tissue due to co-delivery of syndesomes (syndecan-4 proteoliposomes) with FGF-2 in normal healthy rats. In this study, we used syndesomes to enhance revascularization in the ischemic hind limb of a growth factor resistant mouse model with diabetes, obesity and hyperlipidemia.
We used ob/ob mice fed with high fat diet for 10 weeks. We induced ischemia through femoral artery ligation and implanted alginate beads containing treatments into the surgical site. The recovery of perfusion in the mice was tracked using laser speckle imaging.
After 14 days, the ischemic limbs of the mice treated with FGF-2 with syndesomes had significantly higher perfusion compared to the FGF-2 alone group (A, B). Morphometric analysis on sections from the calf and thigh muscle of the mice demonstrated increased ischemic changes in the ischemic limbs of the FGF-2 alone group. Immunostaining for von Willebrand factor revealed increased neovascularization corresponding with the increase perfusion measured in the FGF-2 with syndesomes group (C, D). Immunostaining for pro-inflammatory M1 macrophage marker CD86 showed similar levels in both treatment groups (E, F). However, immunostaining for pro-wound healing M2 macrophage marker revealed significantly higher levels in the syndesome with FGF-2 treatment group (G, H).
Taken together, these preliminary studies support that co-delivery of syndecan-4 with FGF-2 significantly enhances revascularization in the ischemic hind limb in a clinically relevant diseased mouse model. Our treatment restores the signaling pathway components that are lost due to diseased state causing tissues to become resistant to growth factor therapies.
Abstract 550: Regulation of Macrophage Functions by a Synthetic ROR Ligand
Authors: Billon Cyrielle , Burris Thomas 
Published: March 2022

In the United States, approximately 16 million people suffer from coronary heart disease (CHD) and its various complications. Despite significant research effort and advances in the field of cardiovascular diseases, atherosclerosis remains the leading cause of mortality. Atherosclerosis is a multi-step inflammatory disease characterized at the early steps by accumulation of cholesterol in the arterial wall followed by recruitment of immune cells (macrophages and lymphocytes).
Previous studies suggest that a member of the nuclear receptor family, retinoic-acid-receptor-related orphan receptors alpha (RORα), may play an important role in the development of atherosclerosis but mechanisms are still unclear. Recent work from our lab shows that ROR is involved in inflammatory process. We hypothesize that synthetic ROR ligands can be used as a tool to investigate the role of ROR in the regulation of inflammation and cholesterol handling and could have a therapeutic potential in the treatment of atherosclerosis.
We developed a selective RORα/γ inverse agonist, SR1001, that blocks ROR activity both in vivo and in vitro. To identify the role of ROR in macrophage function, we used bone marrow derived macrophages from WT mice treated with SR1001 or DMSO control. Using an in vitro model of macrophages polarization and bio-molecular techniques, we monitor the effect of ROR in M1/M2 polarization of macrophages and NLRP3-inflammasome activity.
Our results show that the ROR ligand blocks the macrophages M2 polarization and increases M1 function such as cytokines production and secretion. The ROR antagonist induces inflammation by stimulating the caspase-1-activating NLRP3 inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Decreasing M2 polarization and induction of IL-1β is associated with increased atherosclerosis. Thus, Our data suggests that ROR could play a critical role in atherosclerosis development.
In conclusion, ROR could be a good target to fight inflammatory diseases such as atherosclerosis by targeting macrophages.
Abstract 51: Kawasaki disease in a patient with Acute Myeloid Leukemia and Candida infection
Authors: Yamazaki-Nakashimada Marco , Rivas-Larrauri Francisco , Sorcia-Ramirez Giovanni , Zapata Marta , Garrido-García Martín 
Published: March 2022

Though the causative agent of Kawasaki disese (KD) remains unclear, an infectious agent is thought to trigger the disease. KD has been described associated with immunodeficiency disorders including HIV. We report a patient with Acute Myeloid Leukemia (AML) who developed KD in an early course of the disease.
A 4 year-old boy was diagnosed as AML and received treatment with daunorubicin, etoposide and Ara-C. Eleven days later he started presenting fever, diarrhea and abdominal pain. A diagnosis of neutropenic colitis was made and treatment with vancomycin and cefepime was started. He continued having fever and polymorphic eruption was added, with prominent perineal erythema. Later he presented redness of the lips, hands and feet edema, erythema in the palms and soles and conjuctival erythema. The diagnosis of KD was established and treatment with IVIG and low-dose prednisone was administered. Echocardiogram revealed left coronary aneurysm and pericardial effusion. Abdominal-ultrasound showed gallbladder hydrops. Candida grew in blood culture and treatment with amphotericin-B was started.
Akita et al. reported one previous case of leukemia associated with KD. As the previous reported case, our case developed the disease in the induction therapy for the AML. Interestingly, infection with Candida was documented in our patient. Administration of Candida cell Wall-antigens induced KD-like coronary vasculitis in mice. C. abicans colonizes the intestinal tract and causes invasive deep micosis in an immune-compromised host. Beta-glucan from the fungus stimulates the host immune system inducing an inflammatory response. Sampling campaigns over Japan during the KD season detected major differences in the microbiota of the tropospheric aerosols, with the unexpected finding of the Candida species as the dominant fungus from aloft samples (54% of all fungal strains). These results, provide support for the feasibility of a windborne pathogen. A fungal toxin could be pursued as a possible etiologic agent of KD. To our knowledge this is the second case of KD associated with leukemia. Chemotherapy-induced immunosuppresion could have a role in the genesis of KD in our patient and possibly triggered by a Candida infection.
Abstract 15933: Scn5a Gating Pore Current Causes Cardiac Arrhythmias Associated With Dilated Cardiomyopathy
Authors: Moreau Adrien , Mercier Aurélie , Gosselin-Badaroudine Pascal , Burger Bettina , Keller Dagmar I , Chahine Mohamed 
Published: March 2022

Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers, impairs cardiac contractility and systolic function leading to heart failure. SCN5A gene encodes the cardiac sodium channel (Nav1.5) in which mutations have been identified in patients with arrhythmic disorders associated with DCM. However, it is not understood how a dysfunction in SCN5A may cause very atypical cardiac arrhythmias associated with dilatation remodeling of the heart.
We generated control and patient specific human induced pluripotent cells (hiPS) carrying the Nav1.5/R219H mutation. hiPS were differentiated to obtain cardiomyocytes derived from hiPS (hiPS-CM). Molecular dynamic simulations experiments revealed that the R219H mutation opens up a pathway directly through the voltage sensitive domain (VSD) of Nav1.5 channels. We hypothesized that such a proton leak through the VSD caused by the R219H mutation may be responsible for the clinical phenotypes observed in our index patient. We unraveled the underlying mechanism responsible for the association of SCN5A and DCM. Indeed, the data shows the presence of a gating pore or omega current that is responsible of the observed abnormal ionic homeostasis, absent in control hiPS-CM. Action potential recordings showed abnormal electrical activities in both atrial and ventricular hiPS-CM. Myocytes stemmed from the index patient exhibited dilatation. Single cardiomyocytes contractility probed using atomic force microscopy revealed a higher frequency of contractility with reduced force compared to control myocytes. This could be attributed to the observed contractile protein dysfunction uncovered using immunofluorescence.
Overall, the results support the hypothesis that the Nav1.5/R219H mutation creates a proton leak. This leak then causes electrical, structural and contractile disturbances that may explain the related cardiac arrhythmias associated with myocytes dilatation.
We concluded that gating pore current, a novel cardiac channelopathy is directly related to the association of SCN5A and DCM. We suggest that this aberrant leak current should be investigated to characterize similar SCN5A mutations with similar clinical phenotypes.
Abstract 16047: Novel Association of Polymorphic Genetic Variants With Baseline PR Interval in Patients With Atrial Fibrillation: New Directions From a Prospective Study (DECAF)
Authors: Mohanty Sanghamitra , Hall Amelia W , Mohanty Prasant , Trivedi Chintan , Di Biase Luigi , Bai Rong , Al-Ahmad Amin , Horton Rodney , Burkhardt John David , Sanchez Javier , Zagrodzky Jason , Bailey Shane , Gallinghouse G. J , Hranitzky Patrick , Iyer Vishwanath R , Natale Andrea 
Published: March 2022

Background:
Prolongation of the PR interval in the electrocardiogram (ECG) is known to be associated with increased risk of atrial fibrillation (AF). We examined the association of selected single nucleotide polymorphisms (SNPs) with PR interval in AF patients.

Methods:
Four hundred AF patients undergoing catheter ablation were prospectively enrolled at our center. DNA extraction and genotyping for 16 AF-related SNPS from blood samples were performed using Qiagen QiaAMP kit and TaqMan assay respectively. A total of 371 DNA samples were available for genotyping. Multivariate linear regression analyses (after adjusting for age, gender, BMI, AF type) were applied to test allelic association (for minor allelic frequency) with baseline PR interval. PR interval duration in millisecond (ms) was derived from 12-lead ECGs recorded at the time of patient enrollment.

Results:
Three hundred seventy-one AF patients (67% male, 62±12 year, left atrial size 45.3±7 mm, 64% non-paroxysmal) undergoing catheter ablation were included in the analysis. Two SNPs, rs3807989 and rs7193343 were identified to have significant association with baseline PR interval.

For rs3807989 (7q31), median [interquartile range] of PR interval durations were 174 (149-202), 169 (145-194), 162 (137-184) ms for AA, AG, GG (risk allele: A) respectively. The regression analysis for rs3807989 in a dominant model, showed significant allelic association (regression coefficient (beta) 9.8 [95% CI 1.58 to 18.02], p=0.019) with prolonged PR interval.
For rs7193343, median [interquartile range] of PR interval durations were 169 (144-194), 162 (142-184), 154 (128-186) ms for CC, CT, TT (risk allele: T) respectively. When considering the effect of rs7193343 fitted with an additive model, significant inverse association with PR interval was observed (beta -7.4 [95% CI -14.23 to -2.63], p=0.032).

Conclusion:
We identified two novel genetic markers located near developmental genes CAV1 and ZFHX3 to be associated with PR interval; rs3807989 correlated directly with prolonged PR duration while rs7193343 demonstrated inverse correlation with the phenotype. Defining the etiology of this differential association will provide important insight into underlying AF mechanisms.
Abstract 17855: Prognostic Impact of Coronary Revascularization in Acute Coronary Syndrome Patients With Cardiogenic Shock
Authors: Sakamoto Kazuo , Matoba Tetsuya , Mohri Masahiro , Tanaka Nobuhiro , Hokama Yohei , Fukutomi Motoki , Hashiba Katsutaka , Fukuhara Rei , Ueki Yasushi , Suwa Satoru , Matsuura Hirohide , Tachibana Eizo , Yonemoto Naohiro , Nagao Ken ,   JCS Shock Registry Scientific Committee
Published: March 2022

Background:
Randomized trials have shown that coronary revascularization benefits patients with acute coronary syndrome (ACS). Furthermore, recent studies reported that revascularization could improve the outcome even in high-risk patients. We investigated the prognostic impact of revascularization and the factors that abandon the invasive strategy in patients with ACS complicated with cardiogenic shock.

Methods and results:
The Japanese Circulation Society Cardiovascular Shock registry (JCS-Shock registry) was a prospective, observational, multi-center, cohort study. Between May, 2012 and June, 2014, a total of 980 patients with cardiovascular shock were enrolled from 82 centers in Japan. We assessed the prognostic impact of coronary revascularization in ACS patients in JCS-Shock registry. The primary endpoint was all cause mortality at 30 days after administration.

Among 495 subjects with ACS (ST-segment elevation acute myocardial infarction (STEMI) 408, Non-ST-segment elevation ACS (NSTEACS) 87), emergent coronary angiography was carried out in 448 (90.9%) subjects and any revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)) was performed in 411 (83.0%) subjects.
Thirty-day mortality in subjects treated with PCI and/or CABG (Revasc group) was 29.8% and neither PCI nor CABG (Non-Revasc group) was 51.2% (n=84, 17.0%) (P=0.0015 by Chi-square test), suggesting a beneficial effect of revascularization. Baseline characteristics of subgroups in Revasc or Non-Revasc were significantly different in age (71.0 vs. 76.5, P<0.0037), female gender (23.2% vs. 40.5%, P=0.0016), previous PCI (66.7% vs. 39.1%, P<0.0276), STEACS (86.8% vs. 60.7%, P<0.0001).

Conclusions:
In the JCS Shock registry that observed contemporary emergency cardiovascular care in Japan, 30-day mortality of ACS complicated with cardiogenic shock was lower in patients underwent coronary revascularization compared with patients without any revascularization. Revascularization was less performed in elderly, female, patients without previous PCI and NSTEACS patients, associated with unfavorable outcomes. We may reconsider the therapeutic strategy to benefit patients by coronary revascularization.
Abstract 18044: Predictors of Bicuspid Aortic Valve Associated Aortopathy in Pediatric Patients
Authors: Grattan Michael , Prince Andrea , Franco-Cereceda Anders , Petrovic Michele , Mohamed Salah A , Loeys Bart , Dietz Harry , Mital Seema , Manlhiot Cedric , Andelfinger Gregor , Mertens Luc 
Published: March 2022

Bicuspid aortic valve (BAV) is the most common congenital heart disease and is commonly associated with significant ascending aorta dilation. Valve morphology and function have been proposed as potential risk factors; however evaluating their role is difficult, as BAV morphology and valve function are inherently related. Our objective was to determine whether BAV morphology and function are independently associated with ascending aorta dilation in pediatric patients.
We performed a multicenter, retrospective, cross-sectional study of pediatric patients with BAV that were followed after 2003. The last patient echocardiogram prior to valve intervention was analyzed for BAV morphology, presence and severity of aortic stenosis (AS) and insufficiency (AI), and aortic root and ascending aorta dimensions. The relationship of potential risk factors to ascending aorta dimensions at different ages was determined using linear regression.
Data was obtained from 1725 patients (68% male). The most common BAV morphology was right-left (R-L) coronary cusp fusion (65%) followed by right-non (R-N) fusion (34%) and left-non fusion (1%). Fourteen percent of patients had at least moderate AS and 7% had at least moderate AI. R-L fusion was associated with coarctation (55%), while R-N fusion was less associated with coarctation (19%) and more associated with valve dysfunction (24% and 12% with at least moderate AS and AI). Twenty-seven percent of patients had significant ascending aorta dilation (Z score >3). AS and AI were associated with more significant ascending aorta dilation and a faster Z-score progression over time. R-N fusion was associated with ascending aorta dilation; however, when valves with AS and AI were excluded, there were no differences related to morphology. In patients with no AS or AI, 15% had significant ascending aorta dilation.
In this large pediatric cohort of patients with BAV, we show that valve morphology is not independently associated with ascending aorta dilation. Valve dysfunction (both AS and AI) is associated with more significant dilation; however, even in valves with normal function, there is significant ascending aorta dilation. We suggest that there is an inherent arterial abnormality, possibly modified by aortic flow patterns.