bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 18332: EphrinB2/EphB4 Signaling controls the Dose-Dependent Switch between Normal and Aberrant Angiogenesis by VEGF
Authors: Groppa Elena , Sacchi Veronica , Brkic Sime , Trani Marianna , Heberer Michael , Gianni-Barrera Roberto , Banfi Andrea 
Published: July 2021

Vascular Endothelial Growth Factor-A (VEGF) is the master regulator of vascular growth and it can induce either normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo, and not on the total amount. However, stimulation of pericyte recruitment by co-expression of Platelet Derived Growth Factor-BB (PDGF-BB) could prevent aberrant structures despite heterogeneous and high VEGF levels and switch to homogeneously normal angiogenesis.
Here we dissected the role of specific pericyte-mediated signaling pathways in the switch between normal and aberrant angiogenesis by VEGF.
Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses, inducing either normal or aberrant angiogenesis, and were further transduced to secrete soluble blockers of the TGFβ-1/TGFβ-R, Tie2/Angiopoietin or EphB4/EphrinB2 pathways (LAP, sTie2Fc and sEphB4, respectively). Two weeks after implantation into mouse limb muscles, neither TGFβ nor Angiopoietin blockade altered the normal angiogenesis by low VEGF, whereas EphrinB2/EphB4 inhibition caused a switch to aberrant angioma-like structures, similar to the effects of blocking pericyte recruitment. Conversely, gain-of-function of EphB4 signaling by systemic treatment with recombinant EphrinB2-Fc completely prevented aberrant angiogenesis by high VEGF levels and yielded normal networks of mature capillaries.
We recently found that VEGF over-expression in muscle induces angiogenesis without sprouting, but by circumferential enlargement and longitudinal splitting (intussusception). EphB4 inhibition increased both endothelial proliferation and the diameter of initial enlargements induced by low VEGF (4 days), leading to a failure of splitting and progressive angioma growth. However, it did not interfere with pericyte recruitment, contrary to high VEGF alone. Conversely, EphB4 stimulation decreased both endothelial proliferation and the diameter of enlargements induced by high VEGF to values similar to low VEGF alone, and accelerated splitting into pericyte-covered capillary networks.
In conclusion, EphrinB2/EphB4 signaling can prevent VEGF-induced aberrant angiogenesis by regulating intussusception.
Abstract 20450: Impact of Addressing Social and Behavioral Factors in Reducing Heart Failure Readmission
Authors: Milani Richard V , Lavie Carl J , Ventura Hector O 
Published: July 2021

Background:
United States 30-day hospital readmission rate (RR) for heart failure (HF) is averaging 22.6% and represents a financial burden for CMS and now to hospitals via potential penalties leveraged by Medicare. Efforts to improve RR must identify and treat underlying causes, and these may include social and behavioral factors not heretofore discerned.

Methods:
We evaluated multiple social and behavioral factors using validated questionnaires in 74 consecutive patients admitted for HF to determine their prevalence and their possible influence over HF admissions including 30-day readmission. Measures included depression, medication adherence, quantified sodium consumption, heart failure quality of life, sleep-related concerns, and other socio-economic factors including medication affordability and family support. Specific problems were systematically addressed during hospitalization and follow-up. In addition, patients were closely monitored during the 30-days post-discharge with oral diuretics adjusted as needed based in change in daily weight.

Results:
The average age was 71±13 years, 61% were male, and the mean ejection fraction was 36 ±19%.

Frequently admitted patients (≥ 2 HF admissions in the last 12 months) differed from standard patients:

*p<0.05, †p=0.10
The combination of addressing and treating these factors reduced subsequent 30-day readmission from 25% to 12% (p<0.05).

Conclusions:
Social and behavioral issues are commonly found in HF patients and are more prevalent in patients with a high frequency of HF hospitalizations. Identifying and systematically addressing these factors can lead to a reduction in hospital utilization.
Abstract 43: Could Serum Lactate Level Predict Neurological Outcome in Patients Undergoing Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest?
Authors: Verginella Francesca , Scamperle Alice , Rossini Perla , Zuliani Michele , Campanile Vincenzo , Peratoner Alberto , Alongi Fabio Salvatore ,   Ice 2 Group
Published: July 2021

Until November 2013 and the printing of TTM trial, TH was a standard of treatment in OHCA.
In Italy 55.000 events of CA occur every year. Early Prognostication in neurological outcome is still difficult and controversial. We decided to investigate the influence of lactacidemia at the time of start(T0) TH and after 24 hours(T24) on neurological outcome at 6 months.

After the ischemic injury, microcirculation is dysfunctional. Lactacidemia explains how the microcirculation is going to restore itself
1,2
.

Methods:
We did a retrospective analysis of 88 patients admitted to several Italian ICUs. Patients underwent TH trough endovascular or surface cooling. We tested lactate in mmol/L at ICU admission and after 24 hours. Neurological outcome was measured using the Pittsburgh Cerebral Performance Category Scale (CPC) by phone-interview. We analysed the data using the ROC curve.

Results:
The mean value of Lactate at T0 was 5,7 mmol/L and and at T24 was 3,6 mmol/L. 47 patients had a good neurological outcome (CPC score of 1-2). 41 patients had a bad neurological outcome (CPC score 3-5).

Discussion and Conclusion:
At T0 the AUC is 0,69, P value is 0,001. At T24 the AUC is 0,56, P value is 0,288.

Lower serum lactate at T0 is weakly associated with CPC 1-2 at 6 months. On the contrary there is no correlation between lower serum lactate at T24 and good neurological outcome. This conclusion is in contrast with current evidence based in literature
3
.

Despite Lactacidemia being a sign of microcirculatory damage, our study explains that Lactate at T24 can not be used to predict the neurological outcome. More studies are needed to explain if Lactates Level could be a strong prognostication index.

1
“Post-cardiac arrest syndrome” Nolan et al. Resuscitation 2008;79

2
“Microcirculation during CA and resuscitation” Fries M, et al. Crit Care Med 2006;34

3
“Association of serum lactate and survival outcomes in patients undergoing

TH after CA” Starodub et al; Resuscitation 2013;84
Abstract 144: Lung Parenchymal Consolidation during typical Kawasaki Disease
Authors: Sato Seiichi 
Published: July 2021

Introduction:
Kawasaki disease (KD) is a systemic vasculitis of childhood throughout the body. We report a patient who complicated by severe pneumonia of lung parenchymal consolidation (LPC) during typical KD clinical course.

Case reports:
A 7-yr-old male who had a past history of KD at 3-yr-old, visited a general practitioner with fever, sore throat and neck pain. Three days later, after being treated with CTRX/TBPMPI, he was transferred to our hospital because of bilateral lymph nodes swelling and a generalized erythema and rash.

On admission he was still febrile and had bilateral conjunctival injections, cervical and axillary lymphadenopathy and markedly reddened pharynx, without edema. We diagnosed him as KD and treated him with aspirin and IVIG at a dose of 2.0g/kg, but the condition worsened; he developed dyspnea and dry cough. Crackles were noted on rt-lung auscultation, along with rt-basal dullness to percussion of the thorax.
Chest radiography and a subsequent computed tomography scan revealed disseminated patchy infiltrates and ground-glass alterations with massive pleural effusions on rt-lung, and enlarged axillary and mediastinal lymph nodes.
Some kinds of microbiology (including Mycoplasma) and virology (Epstein-Barr virus, cytomegalovirus, parvovirus B19), from all sampled sites (pleural effusion, blood, pharyngeal swab and cerebrospinal fluid), were negative for pathogenic specimens.
So we treated him as intractable KD with second-IVIG and m-PSL, which led to the quick resolution of fever and progressive amelioration of pneumonia. Echocardiography showed normal ventricular size and function without coronary artery lesion (CAL). Thereafter, he was finally afebrile. At the first follow-up visit, 1 month after discharge, he had fully recovered. Clinically, echocardiographically and radiographically, no residues were noted.

Conclusion:
Several manifestations of broncho-pulmonary involvement in KD have been described. But there are very few case of LPC. We should consider the possibility that LPC were secondary to pulmonary arteritis.
Abstract 61: Anti-inflammatory Effect Of Resveratrol In Human Coronary Arterial Endothelial Cells Via Autophagy: Implication For The Treatment Of Kawasaki Disease
Authors: Huang Fu-Chen Huang , Kuo Ho-Chang , Yu Hong-Ren 
Published: July 2021

Kawasaki disease (KD) is an acute febrile vasculitis of childhood and is the leading cause of acquired heart disease in children in the developed world. If untreated, KD can result in coronary aneurysms in 25% of patients, who are at risk of myocardial infarction, sudden death, and congestive heart failure. Despite the success, 10-20% of children will have persistent or recrudescent fever after their first infusion of IVIG. These patients are at increased risk of developing coronary artery abnormalities. Additional therapies should be explored to decrease the incidence of coronary arteritis complication and improve the prognosis in Kawasaki disease. Induced autophagy with resveratrol confers cardioprotection during ischemia and reperfusion in rats.
KD is associated with elevated production of inflammatory cytokines, causing damage to the coronary arteries. Serum TNF-alpha levels are elevated in KD, which was supposed to activate the endothelial cells. As a result, adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1(VCAM-1) are expressed in the endothelial cells, and leucocytes adhere firmly to endothelial cells. The leucocytes then damage the endothelial cells and smooth muscle cells and cause vasculitis.
In this study, we examined the anti-inflammatory effects of resveratrol on TNF-alpha-induced adhesion molecule expression (VCAM-1 and ICAM-1) and cytokine production (interleukin (IL)-1beta, IL-6 and IL-8) in HCAECs. Pretreatment with resveratrol significantly inhibited TNF-alpha-induced adhesion molecules and cytokines production in HCAECs via the activation of autophagy. Our results suggest that adjunctive resveratrol therapy may modulate the inflammatory response during KD vasculitis and explore the role of autophagy in the pathogenesis of the complication and the promising therapy.
Abstract 11138: Superresolution Studies of Sodium Channels Within Intercalated Disk Microdomains Suggest Novel Arrhythmia Mechanism
Authors: Veeraraghavan Rengasayee , Lin Joyce T , Keener James P , Poelzing Steven , Gourdie Robert G 
Published: July 2021

Pore-forming (Nav1.5) and auxiliary (β1; SCN1b) subunits of cardiac sodium channels are enriched at the cardiomyocyte intercalated disk (ID). Mathematical models suggest that this may facilitate conduction via ephaptic mechanisms.
We recently demonstrated Nav1.5 enrichment (gSTED superresolution microscopy) and close membrane apposition (<10 nm; electron microscopy) within the perinexus, a microdomain surrounding connexin43 (Cx43) gap junctions (GJ). These data identified the perinexus as a candidate structure for the cardiac ephapse. Further studies using gSTED and STORM superresolution microscopy revealed Nav1.5 and β1 enrichment within ID regions not containing dense clusters of Cx43 and N-Cadherin. Notably, both were identified within the perinexus: Overall, 22% of Nav1.5 & β1 were located within perinexal regions while only 2 and 5% respectively overlapped with Cx43 clusters. Importantly, acute interstitial edema (AIE) increased intermembrane distance at perinexal, but not at non-perinexal sites in adult guinea pig myocardium. Functionally, this correlated with decreased transverse conduction velocity (CV-T; 15.2±0.3 vs. 19.6±0.1cm/s) and increased anisotropic ratio (AR; 3.0±0.2 vs. 2.8±0.1) relative to control, in perfused guinea pig ventricles. Nav1.5 blockade (0.5 μM flecainide) by itself decreased CV (18%) without changing AR. However, Nav1.5 inhibition during AIE preferentially decreased CV-T (13.0±0.6cm/s), increased AR (3.3±0.2) and increased spontaneous arrhythmias (7/9 vs. 4/11) compared to AIE alone. Notably, only a computer model including ephaptic coupling and the ID localization of Nav1.5 could recapitulate these results. Next we investigated the role of β1 in ephaptic coupling: Electrical cell-substrate impedance spectroscopy of 1610 cells heterologously overexpressing β1 revealed 3-fold higher paracellular resistance relative to native 1610 cells.
These data along with the known cell adhesion function of β1 in neural tissue suggest that β1-mediated adhesion may facilitate close membrane apposition within the perinexus. Taken together, our results identify β1-mediated adhesion as a novel determinant of anisotropic conduction and potential antiarrhythmic target.
Abstract 11415: Enhancing Direct Cardiac Reprogramming Efficiency Using Small Molecules
Authors: Mohamed Tamer M , Stone Nicole , Berry Emily , Wang Haixia , Ding Sheng , Srivastava Deepak 
Published: July 2021

The ability to directly trans-differentiate fibroblasts into cardiomyocytes through overexpression of three core transcription factors, Gata4, Mef2C &TBX5 (GMT), has been demonstrated by our group and others. Direct cardiac reprogramming has great potential to treat heart failure. However, clinical application remains limited due to inefficiencies in the reprogramming process and immaturity of the differentiated cardiomyocytes. In the current work, using a chemical approach we aim to increase the efficiency and the maturation of these directly reprogrammed cardiomyocytes.
We have optimized a high-throughput screening method in 384-well plates using an alpha-MHC-GFP reporter to detect cardiac reprogramming in mouse cardiac fibroblasts. We screened 5500 compounds and identified 20 hits which have increased the reprogramming efficiency by 2-6 fold compared to controls. Among these top hits, 4 TGF-β inhibitors (DS 1-4) and 4 WNT inhibitors (DS 5-8) enhanced direct cardiac reprogramming. Further in depth investigations showed that the combination of the TGF-β inhibitor DS1 and the WNT inhibitor DS5 increased reprogramming efficiency 7 fold when added to the GMT-overexpressing fibroblasts on the first day of reprogramming. This combination of small molecules also enhanced the maturation of the reprogrammed cells, as we observed beating cells after only 1 week of reprogramming compared to 6–8 weeks without the small molecules. Activation of canonical WNT signaling or TGF-β signaling significantly abrogates the improvement in cardiac reprogramming by DS1 and DS5. These results indicate the specificity of the action of these inhibitors through the canonical WNT and TGF-β pathways. In a translational effort, we injected DS1, 2 and 5 intraperitoneally in mice for 2 weeks in combination with GMT following myocardial infarction (MI) and found a significant improvement in cardiac function as represented by an ejection fraction of 39.11% ±1.2% in the GMT + compounds group vs. 28.44% ± 3.98% in the GMT only group (p<0.05), 6 weeks after MI compared to an ejection fraction of 22.72% in the control untreated group.
In conclusion, small molecules, especially the TGF-β inhibitors and WNT inhibitors, greatly enhanced direct reprogramming in vitro and in vivo.
Abstract 13189: CV-Ecosystem Model: Workplace Wellness With Individualized Medicine
Authors: Krittanawong Chayakrit , Kermott Cindy A , Wang Zhen , Zhang HongJu , Marysia Tweet S , Chirapongsathorn Sakkarin , Hayes Sharonne 
Published: July 2021

Introduction:
At-work stress is rapidly becoming a significant contributory cause of occupational disease, while sedentary work and dietary indiscretion, taken together, have contributed to cardiovascular disease, known to be associated with substantial morbidity and mortality. The aim of the CV-Ecosystem Model is to provide an individual approach by systematic environmental modification of the work site.

Methods and Results:
Our model which we term the CV-Ecosystem Model includes two basic tenets: 1) Workstation technologic design 2) Flexible physiologic activity.

Workstation technologic design utilizes the services of a certified Ergonomist to engineer a comfortable, safe, and effective work environment. It is tailored to the unique physiologic needs of the worker while enhancing productivity within different environments. Computer aided design software would evaluate ergonomics to maximally mitigate the risk and incidence of eye strain, musculoskeletal disorders, repetitive movement disorders such as Carpal Tunnel Syndrome, etc unique to that work activity.
Flexible physiologic activity would permit a worker to actively focus on basic needs during work time, on site; this would include exercise activity and food intake, channeled into healthy options. Exercise time would provide a sense of calm during stressful projects and enhance emotional well-being. In this regard, a three hour period of time, weekly, could be allocated to fitness or meditation. Conveniently located food stations could provide a variety of healthy, plant-based, fresh food options. Both would come with flexible, relative control and scheduling of these activities, within a social environment and context.

Conclusions:
The CV Ecosystem Model, due to its simple technology and relative low cost, could be successfully implemented in a number of enterprises, including all healthcare facilities, with benefit to employee health, wellbeing, and favorable to the business bottom line.
Abstract 13742: PDE3 Inhibitor, Cilostazol, Ameliorates Ischemic Hindlimb Through cAMP and PPARγ Activation
Authors: Sanada Fumihiro , Taniyama Yoshiaki , Muratsu Jyun , Ikeda-Iwabu Yuka , Otsu Rei , Rakugi Hiromi , Morishita Ryuichi 
Published: July 2021

Peripheral arterial disease (PAD) is highly prevalent in the elderly and subjects with atherosclerotic risk factors. Approximately 2-4% of those affected with PAD commonly complain of intermittent claudication (IC) that is a strong indicator for the development of systemic atherosclerosis. Cilostazol (CSZ) has been shown to be of benefit in improving pain-free walking distance and quality of life in patients with IC. CSZ may be the most clinically effective pharmacologic option for IC. However, the underlying mechanism for amelioration of IC by CSZ remains largely unclear.
Here, we demonstrate that CSZ increases expression of hepatocyte growth factor (HGF) in vascular smooth muscle cells (SMCs) via two distinct pathways, PPAR γ and cAMP pathway. Activation of PPAR γ and cAMP activates HGF promoter leading to increase in capillary density and improvement of perfusion in mouse ischemic hind limb model. Enhancement of angiogenesis by CSZ involves Akt/eNOS activation in endothelial cells by HGF secreted from SMCs. However, this process was essentially absent in aspirin treatment group and CSZ with HGF neutralizing antibody treatment group. As CSZ also increases HGF protein production in interstitial area of skeletal muscle where satellite cells reside, we postulated that CSZ stimulates myogenesis. To proof this hypothesis, BrdU was injected every day for 7days in mouse hind limb model, and animals were sacrificed at day 7 and 28. Embryonic form of myocyte heavy chain (eMHC), BrdU positive myocyte, and nuclear centralization was measured. As predicted, CSZ increases the number of newly formed myocyte in ischemic leg compared to control and Aspirin treated mouse. This beneficial effect of CSZ was blunted by the administration of HGF neutralizing antibody. Additionally, Heart specific HGF overexpression mouse in which serum level of HGF is 4-5 times higher than wild type mouse were generated to proof the role of HGF in angiogenesis and myogenesis. Similar to the data obtained from CSZ treated mouse, HGF Tg mouse ameliorates ischemic hind limb via both angiogenesis and myogenesis.
Altogether, our date demonstrates that CSZ improves ischemic hind limb via angiogenesis and myogenesis. This results may account for the beneficial effect of CSZ in PAD patients with IC.
Abstract 15890: Spatiotemporal Analysis of Phase and Frequency Dynamics in Human Persistent Atrial Fibrillation
Authors: Dastagir Nawshin , Vanheusden Frederique J , Chu Gavin S , Salinet João L , Li Xin , Almeida Tiago P , Stafford Peter J , Schlindwein Fernando S , Ng G A 
Published: July 2021

There is increasing focus on understanding the substrates that maintain persistent atrial fibrillation (persAF) based on dominant frequency (DF) sources and phase singularity points (PS). In this study we aimed to combine these two parameters and study the relationship between them to depict the complex spatiotemporal patterns of fibrillation.
For 9 patients with longstanding persAF (duration: 34 ± 25 months) undergoing left atrial (LA) ablation, noncontact array catheter (EnSite Array, St. Jude Medical) was used to collect virtual unipolar electrograms (EGMs) simultaneously from 2048 nodes on the LA. After QRST subtraction, 3D DF maps were obtained through the fast Fourier Transform applied simultaneously to each individual EGM. DF was defined within the range of 4-10Hz (4s time window; 87.5% overlap; 30s/patient). Highest DF (HDF) regions for each individual window were defined as any LA geometry nodes where the calculated DF was within 0.25 Hz of the maximum DF value registered in the window. In order to correlate these HDF locations with PS, phase maps were constructed using the Hilbert transform approach and the locations of PS and its respective chirality (+ clockwise; - anticlockwise) were identified applying an automatic PS detection algorithm.
A statistical majority of PSs (92.5%, p<0.001) were distributed outside the HDF regions. There was a relationship between PSs and the HDF regions such that PSs of opposite chirality influence the propagation of HDF. This was observed for all patients and in 72.1 (± 10.5) % of the total windows. The influence of direction of HDF movement by PSs of opposite chirality was observed 12 (±9) times for each window. A case illustration is presented on Figure 1.
Our analysis suggests an organised behaviour of PS of opposite chirality and HDF regions travelling between them. Once an electrophysiological relationship is established, the spatiotemporal behaviour of PS and HDF could provide alternative ablation strategies for AF.