bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4464Significative role of edoxaban on endotelial cell functions
Authors: Mosquera-Garrote N , Almenglo C , Gonzalez-Peteiro M , Gonzalez-Juanatey J R , Alvarez Castro E 
Published: October 2019

Abstract

Background
Edoxaban is a new oral anticoagulant with factor X activated (FXa) inhibition properties. It is approved for the prevention of ictus and embolism in patients with atrial fibrillation and for the treatment of venous thrombosis and lung embolism. However, little is known about its effects on endothelial cell functions.

Objectives
To study the edoxaban effects on key endothelial functions as proliferation, wound-healing, angiogenesis and peripheral blood mononuclear cells (PBMCs) adhesion.

Methods
Human umbilical endothelial cells (HUVECs) were obtained from donated umbilical cords after signed informed consent of the mothers. Cell proliferation and viability were measured by a real-time cell analyzer by noninvasive electrical impedance monitoring. Migration was study in wound-healing assays. Angiogenesis was measured after 16 hours of HUVECs' seeding in a three dimensional matrix and PBMCs adhesion to HUVECs' monolayers was assessed in the presence or in the absence of edoxaban and/or FXa. Measurements on each assay was compared between control conditions and edoxaban's or FXa's treatments and between treatments with FXa and the combination of FXa and edoxaban.

Results
Edoxaban (1 Nm – 1 μm) was a safe, non-toxic molecule for HUVECs. It significantly promoted HUVECs' growth at concentrations between 10–500 Nm, been the maximal response at 100 nM. The proliferative effect of edoxaban 100 nM was also observed in the presence of FXa 9 nM, which also induced proliferation by itself. In spite of this proliferative effect, edoxaban (50–100 nM) did not increased healing (cells' migration) after a wound, but counteracted the healing effects of FXa 9 nM. Edoxaban (100–500 nM) alone did not influence angiogenesis, but partially restore the anti-angiogenic effect of FXa on HUVECs. Finally, and very interestingly, edoxaban (50–500 nM) significantly inhibited PBMCs adhesion to endothelial cells' monolayers, and even blocked the FXa (50 nM)- and tumor necrosis factor (TNF; 10μg/ml)-induced adhesion.
PBMCs adhesion to endothelial cells

Conclusions
Edoxaban is a safe and proliferative-inducer drug in endothelial cells in vitro. It counteracts the anti-angiogenic and pro-migratory effects of FXa on HUVECs, but more importantly, edoxaban significantly reduced PBMCs adhesion to endothelial cells monolayers in comparison to control experiments and compared to stimulated cells, independently of the pro-inflammatory drug used.

Acknowledgement/Funding
Daiichi-Sankyo España S.A.U.
P4465Acute Cardio-Selective Functional Modulation via a Small-Molecule Direct Myosin-Attenuator (MYK-581) Preserves Diaphragmatic Function in vivo: Comparison versus Disopyramide
Authors: Del Rio C L , Roof S , Anto A R , Anderson R L 
Published: October 2019

Abstract

Background
Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility, hindered relaxation, and impaired exercise capacity. Conventional negative inotropes can alleviate enhanced inotropy in HCM, but do not improve ventricular filling and have the potential to further decrease exercise capacity due to their off/on-target systemic effects. Recently, a novel small molecule cardiac-myosin attenuator, Mavacamten, has been shown to normalize hyper-contractility in the setting of HCM. This study evaluated and compared the in vivo functional selectivity of MYK-581, a mavacamten analog, with those of disopyramide (DISO), a commonly-used negative inotrope.

Methods
In vivo, the acute cardiac (left ventricular pressures) and neuro-muscular (force of diaphragmatic and skeletal muscle contractions) responses to MYK-581 (up to 0.5 mg/kg IV) and DISO (up to 10 mg/kg IV) were simultaneously evaluated using anesthetized and mechanically-ventilated Sprague-Dawley rats; diaphragmatic (both intrinsic and phrenic nerve stimulated) and skeletal contractions (stimulated quadriceps) were measured via strain gauges.

Results
MYK-581 decreased indices of systolic function (dP/dtmax: −32±2% and vmax: −14±2%, P<0.05 vs. pre-dose) and increased LV EDV (+9±2%, P<0.05), while preserving EDP (6±1 to 6±1 mmHg), suggesting improved ventricular distensibility. Despite these marked cardiac effects, MYK-581 preserved both diaphragmatic (23.7±2.0 to 23.3±2.2 g) and skeletal in situ function (14.9±1.4 to 13.9±0.8 g). In contrast, DISO at matched levels of negative inotropy (dP/dtmax: −25±2% and vmax: −19±2%, P<0.05 vs. pre-dose) depressed diaphragmatic force (−16±3%, 23.8±1.9 to 19.8±1.2 g, P<0.05). Finally, the cardiac selectivity of MYK-581 was confirmed in kinetic experiments evaluating the Ca2+-activated ATPase activity of both cardiac and diaphragmatic myofibrils.

Conclusions
Direct myosin modulation with MYK-581, a mavacamten analog, is characterized in vivo by reductions in systolic function with preserved filling pressures and improved LV compliance. Moreover, this cardiovascular profile was devoid in vivo of diaphragmatic/skeletal off-target effects that could further hinder exercise capacity in patients with HCM.
P4493Microvesicles from patients with pulmonary arterial hypertension modulate bFGF from endothelial cells
Authors: Aberg M , Khandagale A , Wikstrom G , Siegbahn A , Christersson C 
Published: October 2019

Abstract

Background
Pulmonary Arterial Hypertension (PAH) is a progressive condition with remodeling of precapillary arteries. Cytokines involved in angiogenesis have been found elevated in PAH but the role of proangiogenic factors and their regulation is far from fully understood. Microvesicles (MVs) can act as intercellular messengers and modify cell production of proteins.

Purpose
To evaluate whether MVs from patients with PAH modulate proangiogenic factors in plasma and endothelial cells.

Methods
62 patients with PAH and 20 healthy controls were enrolled in the study. The number of MVs were determined in whole blood by flow cytometry. For in vitro studies, MVs were isolated from plasma and a primary endothelial cell line of human pulmonary artery endothelial cells between passages 3 to 7 were used. Protein levels in plasma and conditioned media were analyzed by electrochemiluminescence whereas protein levels in cell lysates were analyzed by western blot (WB).

Results
The majority of the MVs in whole blood were derived from platelets and patients with PAH had higher concentrations compared to healthy controls (p<0.0001). In plasma both basic Fibroblast Growth Factor (bFGF) and vascular endothelial growth factor receptor 1 (Flt-1) were increased in the patients as compared to healthy controls (median in pg/ml (IQR) Pat. vs Ctrl: bFGF 4.2 (2.5–9.2) vs 1.2 (0.9–2.1); Flt-1 143.0 (88.5–234.5) vs 53.9 (47.7–59.67); p<0.001 for both).
Endothelial cells were incubated with or without MVs for 18 hours and effects were monitored by analyzing eNOS and ICAM-1 levels by WB. Both markers were significantly altered, i.e. an about 50% decrease of eNOS and a 50% increase of ICAM-1, by patient MVs but not by the control MVs. The endothelial cells were then incubated with MVs for 6h, 12h, 24h, and 48h and bFGF and Flt-1 were measured in the conditioned media. The presence in media of both proteins were increased over time, but only bFGF was significantly regulated by MVs from PAH patient as compared to MVs from the control group at 24h (2.8 fold increase) and at 48h (12.7 fold increase).

Conclusions
An increase of two important proangiogenic proteins were found in PAH patients. The MVs from these patients modulate the endothelial response and contribute to a release of bFGF, whereas the Flt-1 levels are regulated by other currently unknown mechanisms. Further studies of the MVs from PAH patients are needed to elucidate how they are involved in the angiogenic process.

Acknowledgement/Funding
Swedish Research Council, Science For Life Laboratory Sweden
P4512Impact of pulmonary artery catheter on all-cause death of patients with acute heart failure with preserved ejection fraction: Short-term results from the PURSUIT-HFpEF registry
Authors: Matsusaki N , Sotomi Y , Kobayashi T , Hayashi T , Takeda Y , Yasumura Y , Yamada T , Uematsu M , Tamaki S , Abe H , Hikoso S , Nakatani D , Hirayama A , Higuchi Y , Sakata Y 
Published: October 2019

Abstract

Background
Appropriate pulmonary artery catheter (PAC) use may effectively decrease mortality in acute heart failure patients. The concept that the pulmonary artery catheter (PAC) is a valuable tool for hemodynamic monitoring when used in appropriately selected patients and by physicians trained well to interpret and apply the data correctly provided has not been evaluated adequately yet in acute heart failure patients with preserved ejection fraction (HFpEF).

Methods
The PERSUIT-HFpEF Registry is a prospective, observational, multicenter cohort study on prognosis of HFpEF in Japan. Patients hospitalized for heart failure (diagnosed by using Framingham criteria) who met both of the following criteria were enrolled: 1) a left ventricular ejection fraction of 50% or more as measured at the local site by echocardiography; 2) an elevated level of N terminal pro brain natriuretic peptide (NT proBNP) (400 pg per milliliter or more) or brain natriuretic peptide (BNP) (100 pg per milliliter or more). In the present study, we evaluated the impact of PAC on all-cause death of the patients with HFpEF. PAC use was left at the discretion of attending physicians.

Results
The PERSUIT-HFpEF Registry enrolled 486 patients (81±9 years, 259 females, mean follow-up duration 198±195 days). Of these, data of PAC usage was available in 434 patients. Patients were further stratified according to use of a PAC: PAC 153 patients vs. non-PAC 281 patients. Length of hospitalization was numerically shorter in the PAC group than in the non-PAC group [20.3±14.7 vs. 22.5±17.4 days, p=0.182]. Kaplan-Meier estimated 1-year all-cause death rate was significantly lower in the PAC group than in the non-PAC group (9.5% vs. 19.1%, p=0.019). PAC use was associated with significant risk reduction of all-cause death [hazard ratio (HR) 0.425, 95% confidence interval (CI), 0.203–0.890, p=0.023] in the crude analysis. The significant risk reduction still existed after multivariate adjustment including potential confounders [HR 0.427, 95% CI, 0.185–0.984, p=0.046]
Kaplan Meier analysis

Conclusions
In the real-world Asian registry data, PAC use was associated with the improved all-cause death rate, suggesting that the PAC might be a useful guidance tool for treatment of the patients with HFpEF.

Acknowledgement/Funding
Roche diagnostics FUJIFILM Toyama Chemical
P4516Incremental prognostic values of cognitive impairment diagnosed by mini-mental state examination and mini-cog in older hospitalized patients with heart failure
Authors: Saito H , Yamashita M , Endo Y , Mizukami A , Yoshioka K , Hashimoto T , Koseki S , Shimode Y , Kitai T , Maekawa E , Kamiya K , Matsue Y 
Published: October 2019

Abstract

Introduction
Cognitive impairment (CI) is associated with worse prognosis in patients with heart failure, especially in the elderly; however, its incremental prognostic ability in pre-existing prognostic models has not been well elucidated. Moreover, although some tools have been proposed for evaluating cognitive function, their difference in prognostic prediction has not been explicitly compared.

Methods
A total of 352 heart failure patients aged ≥75 years admitted to three hospitals were evaluated for their cognitive function using the Mini-Mental State Examination (MMSE) and Mini-cog during index hospitalization. We diagnosed CI if MMSE and Mini-cog were ≤23 and ≤2, respectively. The primary endpoint was all-cause death.

Results
The median age of the entire cohort was 85 (IQR: 80–88) years, and 47.7% of the subjects were male. Based on the MMSE and Mini-cog, the CI was diagnosed in 167 (47.4%) and 159 (45.2%) patients, respectively. The two diagnostic tools showed poor to moderate agreement (Cohen's kappa coefficient: 0.37, 95% CI: 0.27–0.47). During the follow-up period of median 346 (IQR: 195–489) days, 53 patients (15.1%) died. Although the Kaplan-Meier analysis showed that CI diagnosed using Mini-cog (CI-MC) was associated with significantly higher mortality (P=0.001), this association was not significant for CI diagnosed using MMSE (CI-MMSE) (P=0.059). On multivariate Cox regression analysis, CI-MMSE and CI-MC were individually associated with worse prognosis in older heart failure patients even after adjustment for Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk model and log B-type natriuretic peptide levels (CI-MMSE, HR: 2.05 [95% CI: 1.16–3.61]; and CI-MC, HR: 2.57 [95% CI: 1.46–4.53]). The receiver operating characteristic curve analysis for Mini-cog showed significantly higher area under the curve (AUC) than that for MMSE (0.61 vs. 0.52, p=0.045). To test the incremental prognostic capability, models were constructed by individually adding each score to the MAGGIC risk model, and the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were evaluated. CI-MMSE did not show incremental prognostic predictability (NRI: 0.28, p=0.069; IDI: 0.01, p=0.090), whereas CI-MC (NRI: 0.45, p=0.001; IDI: 0.03, p=0.001) did. Adding CI-MC instead of CI-MMSE to the MAGGIC risk model showed significant reclassification improvement (NRI: 0.45, p=0.002, IDI: 0.02, p=0.041).

Conclusion
In older patients with heart failure, CI defined by Mini-Cog is superior in providing additive prognostic value than that defined by CI based on MMSE.

Acknowledgement/Funding
This study is partially funded by Japan Heart Foundation Research Grant and Novartis Research Grants.
P4521C-reactive protein as a predictor for diastolic dysfunction in patients with sleep-disordered breathing
Authors: Lebek S , Tafelmeier M , Schach C , Schopka S , Holzamer A , Schmid C , Maier L S , Arzt M , Wagner S 
Published: October 2019

Abstract

Background
Sleep-disordered breathing (SDB) is often associated with left ventricular diastolic dysfunction, but the mechanisms are poorly understood. SDB may increase systemic inflammation that could induce myocardial fibrosis leading to diastolic dysfunction.

Purpose
Systemic inflammation and diastolic dysfunction were analysed in patients with SDB.

Methods
295 patients undergoing coronary artery bypass grafting were included in the prospective observational trial CONSIDER-AF (NCT02877745). They were screened for SDB in the preoperative night and an apnoea-hypopnea index (AHI) of ≥15/h defined SDB. Preoperative echocardiography was used to measure the ratio of early (E) and late (A) diastolic transmitral flows (E/A), early diastolic mitral annular velocity (E'), the ratio E/E', LA volume index, and tricuspid regurgitation velocity. Left ventricular diastolic dysfunction was graded I-IV according to current guidelines. Patients with ventricular ejection fraction of less than 45% were excluded. We used serum C-reactive protein (CRP) as a marker for systemic inflammation, resulting in a full data set for 170 patients.

Results
In patients with SDB, serum CRP levels were 3.036 mg/L higher than in control patients (95% confidence interval: −0.393–6.466, P=0.082). Intriguingly, the severity of SDB (AHI) correlated significantly with the CRP levels (coefficient B: 0.13±0.06, P=0.021). CRP also correlated with the severity of diastolic dysfunction (coefficient B: 0.010±0.004, P=0.009). Importantly, multivariable linear regression analysis accounting for the potential confounders age, sex, body-mass index, existing atrial fibrillation, diabetes, AHI, and creatinine indicated that CRP was an independent predictor for the severity of diastolic dysfunction (coefficient B: 0.009±0.004, P=0.016). Interestingly, the latter effect was still present considering just patients with SDB (coefficient B: 0.013±0.005, P=0.015, N=72), but was completely abolished in patients without SDB (coefficient B: 0.001±0.007, P=0.912, N=98), indicating a potential SDB-dependence.

Conclusion
Systemic inflammation (CRP) is associated with the severity of SDB (AHI). Interestingly, only in SDB patients CRP predicts significantly and independently the severity of diastolic dysfunction. Consequently, anti-inflammatory therapeutic strategies could be beneficial for patients with SDB and diastolic dysfunction.

Acknowledgement/Funding
This study was supported by Philips Respironics and the Medical Faculty of the University of Regensburg.
P4522Intravascular volume expansion mitigates the impact of impaired renal function and associated clinical outcomes in chronic heart failure
Authors: Miller W 
Published: October 2019

Abstract

Background/Introduction
Intravascular volume is regulated by the kidneys but the interconnection of the extent of volume expansion with renal function and outcomes in patients with chronic HF has not been assessed. Therefore, we evaluated how GFR-defined renal function and HF-related clinical outcomes are impacted by the relative extent of intravascular volume expansion. Our hypothesis was that greater rather than lesser volume expansion would be protective of worse renal function and contribute to better clinical outcomes than mild-moderate volume expansion.

Purpose
Assess the impact of quantitated intravascular volume expansion on heart failure (HF) outcomes in relation to renal function in post-hospital clinically determined “euvolemic” chronic HF patients.

Methods
Blood volume (BV) was prospectively measured in 87 HF patients considered clinically “euvolemic” post-diuresis at the time of hospital discharge using a standardized radiolabeled albumin indicator-dilution technique (Daxor Corp., NY, NY). A volume cut-point of ≥+25% above normal expected BV was used to define the greater degree of volume expansion from more mild-moderate expansion. These volume subgroups were then stratified by cohort median eGFR (46 mL/min/1.73m2) and analyzed for 1-year outcomes of HF-related mortality or 1st re-hospitalization using the Kaplan-Meier method.

Results
Volume expansion ≥+25% was demonstrated in 53% of the cohort at the time of hospital discharge despite hospital diuretic therapy. In this subgroup over 1.0 year of follow-up the risk for the composite outcome was significantly lower than in the group with mild-moderate volume expansion (Log-Rank p=0.017). Further, in the clinical setting of greater volume expansion, worse renal function with eGFR below the cohort median (<46 mL/min/1.73m2) was not associated with increased risk for the composite end-point (Figure). In contrast, low eGFR in the presence of mild-moderate volume expansion stratified risk and was associated with worse outcome relative to a higher eGFR above the median (Figure).
Figure 1

Conclusions
In post-hospital chronic HF patients significant intravascular volume expansion is common, and importantly the extent of BV expansion impacts outcomes including HF-related mortality. However, greater rather than lesser volume expansion appears to favorably mitigate the impact of worse renal function (low eGFR), while normal or mild-moderate expansion does not spare the impact of worse renal function on outcomes. Thus, a favorable degree of volume expansion appears to balance the risks of worse renal function. Volume-kidney interconnections are complex with volume status modulating the impact of impaired renal function on outcomes in chronic HF.

Acknowledgement/Funding
None
P4527Cardiac resynchronization therapy in patients with non-ischemic cardiomyopathy and severe heart failure may influence the development of unstable ventricular tachycardia
Authors: Lebedev D I , Mishkina A I , Lebedeva M V , Popov S V 
Published: October 2019

Abstract

Objective
The aim of the study was to determine the effect of cardiac resynchronization therapy (CRT) on the development of unstable ventricular tachycardia in patients with non-ischemic cardiomyopathy (CMP) and to analyze the potential of radionuclide methods in predicting life-threatening arrhythmias in the background of CRT.

Materials and methods
The study included 100 patients with non-ischemic cardiomyopathy aged from 32 to 75 years (55±12 years). Patients had III functional class of heart failure (HF); left ventricular ejection fraction (LV) (EF) 30.1±3.8%; 6 minutes walk at a distance of 290.5±64.3 m; and the final diastolic volume of the left ventricle (EDV) is 220.7±50.9 ml. Before implantation of the device with CRT and after 1 year, all patients underwent a 24-hour ECG monitoring. Patients were divided into two groups depending on the presence or absence of paroxysms of unstable ventricular tachycardia. The 1st group included 55 patients (55%) with registered paroxysms of unstable ventricular tachycardia with adequate doses of antiarrhythmic drugs. Group 2 consisted of 45 patients (45%) without reported episodes. Prior to CRT, myocardial metabolism defect (MMD) was evaluated in all patients using radionuclide methods.

Results
Control tests were performed 1 year after the onset of CRT and showed positive clinical dynamics: the left ventricular EF increased from 30.1±3.8% to 42.8±4.8% (p≤0.001); functional class decreased from III to II; The 6-minute walking distance increased from 290.5±64.3 m to 377.2±45.3 m (p≤0.001); and LV EDV decreased from 220.7±50.9 ml to 197.9±47.8 ml (p≤0.005). During 1 year of observation in the first group: 48 patients (80%) had no episodes of unstable ventricular tachycardia; In 7 patients (20%), episodes of unstable ventricular tachycardia were recorded. Evaluation of the effect of increasing EF and reducing EDV on the development of VT paroxysms was performed after the distribution of patients with CRT into subgroups based on the presence or absence of VT episodes. The data showed that in patients whose EF increased by 14%, and EDV decreased by 35 ml during 1 year of CRT, there were no VT episodes, even if VT paroxysms were recorded before CRT. Patients who had VT paroxysms showed an increase in EF of only 9% and a decrease in EDV of only 13 ml. Phase 2 of the study was to assess the impact of MMD changes. In the presence of CRT in patients with less than 15% MMD, there were no VT episodes. VT paroxysms were reported in patients whose MMD exceeded 15%.

Conclusions
(1) Effective CRT in patents with non-ischemic cardiomyopathy significantly reduces the number of VT episodes. (2) Improving fatty acid metabolism (LVD MMD less than 15%) in patients with non-ischemic cardiomyopathy reduces the incidence of VT episodes against the background of CRT.