bluuebunny/crossref_metadata_2025_split huggingface dataset:
P690Incidence of events between vitamin K antagonists and direct oral anticoagulants in patients with cancer
Authors: Pardo Sanz A , Rincon L M , De Lara G , Tamayo A , Belarte L C , Cruz A , Contreras H , Guedes P , Huertas S , Portero J , Martinez A , Alddin-Rajjoub E , Marco A , Monteagudo J M , Zamorano J L 
Published: October 2019

Abstract

Background
Balance between embolic and bleeding risk is challenging in patients with cancer. There is a lack of specific recommendations for the use of antithrombotic therapy in oncologic patients with atrial fibrillation (AF).
We aimed to evaluate the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) within patients with breast cancer. We also compared the embolic and bleeding risk, the preventive management and the incidence of events between patients with and without cancer.

Methods
It is an ambispective observational multicentric study that analysed patients with non-valvular AF treated in Oncology and Cardiology Departments in Spain in the period 2011–2018. A total of 1237 female patients with AF were enrolled: 637 with breast cancer and 599 without cancer. The incidence of thromboembolic and major bleeding events according to the antithrombotic strategy with VKAs or DOACs was evaluated in the cohort of 637 patients with cancer. Analysis were conducted using SPSS software V.22.0 and R V.3.5.1, with a two-tailed significance value of 0.05.

Results
Mean follow-up was 3.1 years. Both groups were similar in age, CHA2DS2-VASc and HASB-LED scores. There was no evidence that the incidence of ischemic stroke/systemic embolism differed between patients with cancer treated with AVK and DOAC after CHA2DS2-VASc adjustment: HR 0.91 (95% CI, 0.42–1.99). In addition, no significant differences in the incidence of major bleeding events were found between DOACs and VKA after adjustment for HAS-BLED score: HR 1.53 (95% CI, 0.93–2.53) (Figure 3). Gastrointestinal bleeding was the main source of haemorrhages in both groups (45% of bleedings among patients treated with DOACs and, 37% in VKAs group). Metastatic disease or active chemotherapy were studied as potential covariates but none of them posed any relevant change in the result.
Kaplan-Meier analysis

Conclusions
Cancer patients treated with DOACs did not differ versus those treated with VKAs with regards to stroke or systemic embolism in a model adjusted for CHA2DS2-VASc. Neither significant differences were found for bleeding events in a model adjusted for baseline HASBLED.
P691Left ventricular systolic function in long term survivors of allogeneic hematopoietic stem cell transplantation
Authors: Massey R , Diep P P , Ruud E , Aakhus S , Beitnes J O 
Published: October 2019

Abstract

Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly utilized in young patients. Allo-HSCT usually requires myeloablative therapy that is potentially cardiotoxic. In addition, allo-HSCT survivors have a high prevalence of cardiovascular risk factors.

Purpose
We aim to describe left ventricular systolic function in long term survivors after allo-HSCT.

Methods
This study included 104 patients, aged (mean±SD) 18±10 years at allo-HSCT, and follow-up time was 17±6 years. 74% were sufferers of malignant disease. Pre-transplantation therapies consisted of anthracyclines (AnT) in 44% and mediastinal radiotherapy in 2%. Conditioning regimes consisted of cyclophosphamide with bulsulfsan in 77%. 22% received anti-lymphocyte globulin and 6% received total body irradiation. Left ventricular (LV) function was evaluated by 2D and 3D echocardiography. Healthy controls matched for age, sex and BMI were used in group comparisons. Group comparisons were performed by t-tests and chi-square. A linear regression was used to identify contributing factors to reduced systolic LV function in allo-HSCT survivors.

Results
Most parameters of LV systolic function including 2D and 3D LV ejection fraction (LVEF), global longitudinal strain (GLS), mitral annulus excursion (MAPSE) and s' were all significantly impaired after allo-HSCT as compared to the control group. Significant (p<0.05) contributors to LVEF in the multivariate regression analysis were age, AnT dosage, graft versus host disease (GVHD, occurring in 67%) and hypertension (HT, occurring in 31%).
Allo-HSCT Control p value n 104 55 – Gender (female) 56 (54) 29 (53) 0.89 Age (yr) 35±12 36±11 0.44 BMI (kg/m2) 25±5 24±3 0.57 Fractional Shortening (%) 31±6 32±4 0.26 2D LVEF (%) 55±6 59±3 <0.005 3D LVEF (%) 54±5 58±3 <0.005 MAPSE (mm) 13±2 15±2 <0.005 Mean s' (mm) 81±17 89±17 <0.005 2D GLS (%) −17±2 −20±2 <0.005 Values: mean ± SD or n (%), t-test or chi-square.

Conclusion
LV systolic function is reduced in long term survivors of allo-HSCT. Pre-transplantation AnT, HT and GVHD are significantly associated with increased risk of cardiotoxicity.

Acknowledgement/Funding
Norwegian Cancer Foundation and Norwegian ExtraFoundation for Health and Rehabilitation
P695Impact of atrial fibrillation on 10y all-cause mortality in curatively treated breast cancer patients
Authors: Jacobs J , L'hoyes W , Beckx M , Weltens C , Janssens S , Van Aelst L 
Published: October 2019

Abstract

Background
Contemporary treatment options for breast cancer have significantly improved survival during the last two decades. To estimate cancer survival, current practice typically relies on cancer size and the presence of metastases, whereas cardiovascular comorbidities such as atrial arrhythmias are typically not taken into account.

Aim
To evaluate the incidence of atrial fibrillation and flutter among curatively treated breast cancer patients and assess its impact on survival in an all-comer population at a tertiary care centre.

Methods
In a large, single centre, retrospective study we enrolled all patients with a diagnosis of breast cancer in 2007 and 2008 who received radiation therapy as part of their curative treatment regimen. We performed Kaplan-Meier and Cox survival analyses to calculate mortality risk over 10-year follow up.

Results
We included 1338 patients, 1326 (99.1%) of whom were women. Mean age (± standard deviation) at diagnosis was 57.6±13.4 years and the distribution of left sided breast cancer versus right sided or bilateral breast cancer was 655 (49.0%) patients versus 645 (48.2%) and 38 (2.9%) patients, respectively. A total of 805 (60.1%) patients had at least one ECG recorded during the 10 year follow up. In this subgroup, atrial fibrillation or flutter was present in 70 (8.7%); 23 patients had pre-existing atrial fibrillation or flutter (32.9%), 26 patients had had radiation therapy for left sided breast cancer (37.1%) versus 21 patients for right sided breast cancer (30%; p=0.375 for left versus right sided radiation therapy). Of the total cohort, 327 (24.4%) patients died during 10 year follow-up. In the subgroup with at least a single ECG recording, mortality equaled 44.3% (31/70) in patients with one or more documented episodes of atrial fibrillation or flutter during follow-up, compared to 21.9% (161/735) in patients who remained in sinus rhythm (p<0.0001). In patients with pre-existing atrial fibrillation or flutter, mortality equaled 47.8% (11/23) versus 42.6% (20/47) in patients with atrial fibrillation or flutter manifesting after treatment initiation (p=0.683).
Survival Atrial Fibrillation/Flutter

Conclusion
Atrial fibrillation and flutter are common in patients with curative breast cancer treatment and have a significant impact on overall survival. Our study highlights the impact of cardiac comorbidities on overall survival following cancer treatment and emphasizes the importance of a dedicated cardiac follow-up in cancer survivors.
P710S100A4, a key player in plaque stabilization?
Authors: Sakic A , Ambartsumian N , Klingelhofer J , Kwak B R , Grigorian M , Bochaton-Piallat M.-L 
Published: October 2019

Abstract

During atherosclerosis, intimal smooth muscle cells (SMCs) acquire a synthetic phenotype. We previously isolated spindle-shaped (S) and rhomboid (R) SMCs from porcine coronary artery. R-SMCs display the features of synthetic/dedifferentiated SMCs. S100A4 was identified as being a marker of R-SMCs in vitro and of intimal SMCs, in pig and man.
S-SMCs were treated with multimeric recombinant S100A4, which resulted in partial transition from S- to R-phenotype and NFκB activation. Remarkably, treatment of S-SMCs with multimeric S100A4 and platelet-derived growth factor-BB (PDGF-BB) together induced a complete SMC transition toward a R-phenotype associated with NFκB activation compared with multimeric S100A4 or PDGF-BB alone, likely through toll-like receptor-4 (TLR-4). RNA sequencing showed strong upregulation of pro-inflammatory genes such as granulocyte-macrophage colony stimulating factor (GM-CSF) and matrix-matalloproteinase-3 (MMP-3, Figure A) when cells were treated with multimeric S100A4 and PDGF-BB together compared with multimeric S100A4 or PDGF-BB alone.
In vivo, ApoE−/− mice were fed with high-cholesterol diet for 9 weeks. The 3 last weeks they were injected intraperitoneally with neutralizing monoclonal S100A4 antibody (clone 6B12, n=11) or with control IgG1 (n=12). Neutralization of extracellular S100A4 induced: decreased area of atherosclerotic lesions (Figure B), decreased necrotic core and cholesterol cleft, decreased number of CD68 positive cells and increased number of α-smooth muscle actin (Figure C) and smooth muscle myosin heavy chains-positive cells when compared to control groups.
S100A4 and SMCs
Our results indicate that extracellular S100A4 could be a new target to influence the evolution of atherosclerotic plaque, leading to plaque stabilization.

Acknowledgement/Funding
Swiss National Science Foundation grant #310030_166357/1
P711Histamine promotes atherosclerotic plaque instability via STAT6-dependent macrophage pyroptosis
Authors: Xu L , Yang X , Ding S , Qian J , Ge J 
Published: October 2019

Abstract

Background
Atherosclerotic plaque formation and rupture is the primary cause for cardiovascular diseases. It's known that cell death and inflammation are crucial processes leading to atherosclerosis, which involves an important role of histamine. The aim of the present study is to determine the function of signal transducer and activator of transcription 6 (STAT6) in histamine-induced macrophage pyroptosis and plaque instability.

Methods
We constructed APOE/STAT6 double knock out (DKO) mice via hybridization of ApoE−/− and STAT6−/− mice. 20 ApoE−/− mice (control) and 20 DKO mice were challenged with high-fat diet for 12 weeks while 10 in each group were intraperitoneally infused with histamine (400ug/kg) every other day. The extent and instability of atherosclerotic plaque were determined by oil-red staining, HE staining, immunofluorescence staining and electron microscopy. Changes in subsets of immune cells were evaluated by flow cytometry. Plasma cytokines were assessed by ELISA. Microarray analysis was applied to detect gene expressions while Western blot and real-time PCR was used to assess gene expression levels.

Results
Morphology studies revealed that histamine could promote plaque formation and vulnerability in ApoE−/− mice, whereas this effect was inhibited in DKO mice. FACS data showed that histamine injection could increase CD11b+Ly6Chigh M1 macrophages differentiation and pyroptosis and facilitate foam cells formation in ApoE−/− mice, which was also inhibited in DKO mice. Microarray analysis and in vitro studies exhibited that histamine could induce the up-regulation of pyrotosis-related proteins such as NLRP3, caspase-1 and MMPs via a STAT6-dependent pathway to promote macrophage pyroptosis and foam cell formation.

Conclusions
We have characterized a novel role for histamine in modulating atherosclerotic lesion development and progression. Moreover, our work have figured out the detailed mechanisms by which histamine modulates the pyroptosis of macrophages and the progress of unstable atherosclerotic plaques. We envision that this study may provide several potential therapeutic targets benefit for atherosclerosis treatment.
P718Genome-wide copy number profiling of atherosclerotic plaques
Authors: Sleptcov A , Nazarenko M S , Kazantsev A N , Burkov N N , Skryabin N A , Krakhmal N V , Tashireva L A , Denisov E V , Lebedev I N , Barbarash O L , Puzyrev V P 
Published: October 2019

Abstract

Background
Atherosclerotic plaque formation results from complex cellular interactions in the intima of arteries, which take place between resident cells of the vessel wall (smooth muscle cells (SMC) and endothelial cells) and cells of the immune system (macrophages (MF)). Less well known is the genomic alterations in cells involving in the atherosclerotic process as can be important in plaque progression and instability.

Aim
The main purpose of the study is to assess the spectrum of structural genomic alterations in the tissue of atherosclerotic artery wall and to evaluate of difference between structural variants (SV) in SMC and MF.

Materials and methods
Samples of atherosclerotic plaques of the internal carotid artery (ICA) was collected from patients during endarterectomy (n=100) and the atherosclerotic coronary arteries (ACA) was obtained by coronary artery bypass surgery (n=10, group: bpACA) and by autopsy (n=8, apACA). Specimens were stored in liquid nitrogen. White blood cells (WBC) derived from the same patients. Control group was the health persons with same age (WBC, n=100). The genomic imbalances in bpACA were assessed by array comparative genomic hybridization (array-CGH, CGH Microarray 2x400K). Identified SVs was verified by droplet-digital PCR using TaqMan-assays (reference assay is RNAse P) in bpACA and ICA groups.SMC and MF were immunostained (Anti-Human CD68 Antibody and Alpha-SMA Antibody) and collected by laser capture microdissection of fresh frozen apACA samples (30–40 cells of each per sample). Collected cells were lysed and DNA amplified by whole genome amplification technique along with WBC of the same person, then analyzed by array-CGH.

Results
We found 90 SV in atherosclerotic coronary arteries, 13% of them were no mentioned before in Database of Genomic Variants. We selected interested SVs that contains only one gene (ACACB, ABCC9, ERLIN1, SFMBT1, PRKRA, and SIRPB1). The loss in the 3p21.1 region (SFMBT1) was in 11.48% patients and 8.5% in control group. Among patients who had diabetes mellitus (DM2) had more frequently loss of SFMBT1 (16%) than patients without DM2 (8%). The frequency of gain 2q31.2 (PRKRA) was 6% in patients whereas in control group we identified it in only one person. The frequency of loss 20p13 (SIRPB1) was approx. 67% in both groups. Several aneuploidies were found in MF (9 trisomies and 3 monosomies) and SMCs (1 trisomy and 8 monosomies). In two patients, SMCs had a normal karyotype. The ratio of duplications and deletions in MF and SMCs was 1:0.8 and 1:7, respectively. In MF of 6 patients identified same duplication in chromosome region 9q34.13-q34.2, (arr[hg19] 9q34.13(9:134337452-135931774)x3) about 2Mb in size.

Conclusion
Our study indicates that genomic alterations are diverse in their structure and are widely represented in cells involved in the atherosclerotic process.
P720Atheroprotective effects of 17beta-estradiol are mediated by PPARgamma in human coronary artery smooth muscle cells
Authors: Jehle J , Tiyerili V , Adler S , Groll K , Nickenig G , Becher U M 
Published: October 2019

Abstract

Background
17β-estradiol (E2) mediates vasculoprotection in various preclinical and clinical models of atherosclerosis and neointimal hyperplasia. However, the molecular mechanisms underlying these effects are still not fully elucidated. Previous studies have demonstrated the essential role of the peroxisome-proliferator-activated-receptor-γ (PPARγ) in mediating vasculoprotective effects of E2 in vivo. The aim of the current study was to investigate whether PPARγ is implicated in mediating vasculoprotective mechanisms of E2 in human coronary artery smooth muscle cells (HCASMC).

Methods
Primary HCASMC were purchased and stimulated with E2 [10 nM], the selective estrogen receptor α (ERα) agonist propylpyrazole triol (PPT) [50 nM] and the selective ERα antagonist methyl-piperidino-pyrazole (MPP) [1 μM], respectively. Changes in PPARγ mRNA and protein expression upon stimulation of ERα were assessed by qPCR and Western blot analyses. Nuclear PPARγ protein expression and DNA binding affinity was assessed after the isolation of the nuclear protein fraction. Hereafter, HCASMC were incubated with E2, PPARγ-antagonist GW9662 [1 μM – 30 μM], or both. HCASMC proliferation was assessed by nuclear BrdU staining and reactive oxygen species (ROS) formation was assessed by L-012- and DCF-DA assays.

Results
E2 significantly increased PPARγ expression in HCASMC (1.95±0.41 –fold; n=5; p=0.0335). This effect was mimicked by ERα agonist PPT (1.63±0.27 –fold; n=7; p=0.0489) and was abrogated by co-incubation with ERα antagonist MPP (1.17±0.18 –fold; n=3; pvs. control >0.05). Nuclear PPARγ expression was enhanced by E2 (1.53±0.16 –fold; n=4; pvs. control = 0.0074; Fig. 2A) whereas PPARγ's DNA binding activity to PPRE remained unchanged upon stimulation with E2 (0.94±0.11 –fold; n=4; pvs. control >0.05). Pharmacological inhibition of PI3K/Akt by LY294002 abrogated E2-induced expression of PPARγ (0.24±0.09 –fold; n=3; pvs. E2 = 0.0017), arguing for a PI3K/Akt-dependent activation by E2. The role of PPARγ in mediating vasculoprotective effects of E2 was assessed in functional assays using PPARγ-antagonist GW9662. E2 diminished HCASMC proliferation which was restored by GW9662. While E2 only slightly decreased ROS production by HCASMC, GW9662 significantly increased ROS levels (1,036±169 RLU x s–1 x cell–1 versus 561±99 RLU x s–1 x cell–1; n=5–6; p=0.0287).

Conclusion
In summary, the present study identifies PPARγ as a downstream mediator of E2-related atheroprotective effects in HCASMC. 17β-estradiol regulates vascular PPARγ-expression in HCASMC via the ERα receptor and the PI3K/Akt pathway. PPARγ agonism might be a promising therapeutic strategy to prevent cardiovascular events in postmenopausal women with depleted E2 plasma levels.

Acknowledgement/Funding
This work was supported by the Bonfor program of the University of Bonn [grant number O-109.0057 to JJ].
P721Shear stress induced unfolding of von willebrand factor may be involved in the premature development of myocardial infarction
Authors: Melnikov I , Avtaeva Y , Kozlov S , Nozadze D , Gabbasov Z 
Published: October 2019

Abstract

Background
Normally, von Willebrand factor (vWF) becomes highly reactive with platelets upon unfolding into a fibrillar conformation at critical shear rate (more than 5000 s–1), that may occur in stenotic arteries. At shear rates below critical value (1200–1300 s–1), which occur in intact coronary arteries, normally there is no conformational rearrangement of vWF. Pathologic unfolding of vWF at shear rates below critical value may increase a risk of the development of coronary thrombosis. There is little information on the role of shear stress induced conformational rearrangement of vWF in the development of myocardial infarction in young individuals.

Purpose
To investigate vWF-dependent platelet adhesion of patients with premature myocardial infarction at shear rates below critical value (1200–1300 s–1).

Methods
Using a microfluidic system, we measured platelet adhesion to a fibrinogen-coated optical surface at shear rates of 1200–1300 s–1 during 10 minutes. We assessed platelet-rich plasma of 8 male persons 40–52 years old, who had previous myocardial infarction at the age of 34–39. The control group comprised 6 healthy male volunteers 30–55 years old. We compared the intensity of scattered laser light measured in volts (V) at 10th minute. To study vWF-dependent platelet adhesion, we blocked GPIb receptor with monoclonal antibody to inhibit platelet interaction with vWF. To compare the intensity of vWF-dependent platelet adhesion with normally occurring adhesion to fibrinogen, we blocked GPIIb/IIIa receptor with monoclonal antibody.

Results
The inhibition of GPIb vWF-receptor decreased platelet adhesion to fibrinogen surface at shear rates of 1200–1300 s–1 by 17.8±4.7% in healthy volunteers and by 92±2.8% in persons with premature myocardial infarction (p<0.05). Inhibition of GPIIb/IIIa receptor decreased platelet adhesion by 91.5±3.8% in healthy volunteers and by 97.3±3.2% in persons with premature myocardial infarction.

Conclusion
Pathologic unfolding of vWF at shear rates below critical value may be involved in the development of premature myocardial infarction.

Acknowledgement/Funding
This work was supported by the grant of the Russian Science Foundation (project #16-15-10098)
P722Glycemic control with canagliflozin, a SGLT-2 inhibitor, attenuates atherosclerosis and endothelial dysfunction in diabetic apolipoprotein e-deficient mice
Authors: Rahadian A , Fukuda D , Salim H , Yagi S , Kusunose K , Yamada H , Soeki T , Sata M 
Published: October 2019

Abstract

Background
Canagliflozin is a SGLT-2 inhibitor, a novel type of drug for type 2 diabetes mellitus treatment. Recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events, although the mechanism is still unknown.

Purpose
The aim of our study was to examine the effect of canagliflozin on vascular endothelial cell.

Method
Eight-week-old apolipoprotein E-deficient (ApoE−/−) mice were treated with streptozotocin (STZ, 75 mg/kg/day) in three consecutive days by intraperitoneal injection to induce diabetes. Diabetic ApoE−/− mice were treated with canagliflozin (30 mg/kg/day) by gavage for 12 weeks or 8 weeks to examine its effect on atherosclerosis or endothelial function, respectively.

Results
Canagliflozin significantly decreased blood glucose level (P<0.001), triglyceride level (P<0.05), and total cholesterol level (P<0.05). Sudan IV staining on the aortic arch showed that canagliflozin decreased atherosclerotic lesion progression (P<0.05). Histological analyses using atherosclerotic lesions in the aortic root showed that canagliflozin reduced lipid disposition (P<0.01), macrophage accumulation (P<0.001, and expression of adhesion molecules such as ICAM-1, and VCAM-1 (P<0.01, and P<0.05 respectively). Canagliflozin also attenuated the development of endothelial dysfunction as determined by acetylcholine-dependent vasodilation (P<0.05), and reduced the expression of inflammatory molecules, such as ICAM-1 and VCAM-1 (P<0.01), also MCP-1, F4/80, IL6, and iNOS (P<0.05) in the aorta. Canagliflozin reduced oxidative stress as determined by the reduction of the expression of NOX2, NOX4, p22phox, p47phox in the aorta and by the urinary excretion of 8-OHdG. In in vitro experiment using human umbilical vein endothelial cells (HUVEC), methylglyoxal (MGO), a precursor of advanced glycation end products, significantly increased the expression of inflammatory molecules such as ICAM-1, MCP-1, and p22phox in (P<0.05, respectively). MGO also decreased the phosphorylation of eNOSser1177 and Akt, and increased phosphorylation of P38 MAPK in HUVEC.

Conclusion
Glucose lowering effect by canagliflozin attenuates the development of endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Anti-inflammatory effect due to the reduction of glucose toxicity on endothelial cells might be one of the mechanisms.