bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct oral anti-coagulants in patients with atrial fibrillation and bioprosthetic valve: a meta-analysis of randomized controlled trials
Authors: Abella F , Castro R , Tiongco R H , Rosano A L , Bailon D 
Published: October 2021

Abstract

Background
Patients with atrial fibrillation (AF) and bioprosthetic valve (BPV) are at increased risk for thromboembolic events and require anticoagulation. However, management strategies for these patients have not yet been well addressed by randomized controlled trials (RCTs). For years, warfarin was the only available oral anticoagulant, but this changed with the introduction of the direct oral anticoagulants (DOACs). However, there is no clear consensus about indications for DOACs in these patients due to the lack of prospective trials.

Purpose
The objective of this meta-analysis is to show the efficacy of DOACs in AF patients with BPV in terms of composite cardiovascular outcomes. In addition, the study aims to show the safety of DOACs in terms of major bleeding.

Methods
A comprehensive literature search for randomized controlled trials (RCTs) was performed in MEDLINE, PubMed and Clinicaltrials.gov in human subjects done within 2010 to 2020. Results were pooled using fixed effects. The primary outcome was a composite cardiovascular outcome from all included studies, which include death, major bleeding and major adverse cardiac events (stroke, transient ischemic attack, valve thrombosis, myocardial infarction, systemic embolism, and hospitalization for heart failure). Secondary outcomes include all-cause stroke or systemic embolism, major bleeding, death from cardiovascular cause and all-cause death.

Results
Four RCTs were included in the meta-analysis. DOACs used were Apixaban, Dabigatran, Edoxaban and Rivaroxaban. In patients with AF and BPV, DOACs performed similarly with warfarin in terms of composite cardiovascular outcome (RR 1.01, 95% CI 0.86–1.19, P=0.88, I2=0%). On the other hand, DOACs performed better than warfarin in reduction of all cause stroke and systemic embolism (RR 0.48, 95% CI 0.27–0.87, P=0.01). There is non-statistically significant risk reduction for major bleeding (RR 0.81, 95% CI 0.56–1.17, P=0.26, I2=0%) and other secondary outcomes such as death from cardiovascular causes (RR 0.79, 95% CI 0.39–1.60, P=0.51, I2=0%) and all cause death (RR 0.94, 95% CI 0.55–1.62, P=0.71, I2=0%) showing similar outcomes with NOACs and warfarin.

Conclusion
DOACs compared with warfarin are similar in terms of composite cardiovascular outcome, major bleeding and death. However, DOACs performed better than warfarin in reducing all-cause stroke/systemic embolism and can be an alternative for oral anticoagulation in patients with AF and BPV.

Funding Acknowledgement
Type of funding sources: None. Forest plot for all-cause stroke or systemic embolism
The greek version of the professional quality of life (ProQoL) scale version 5
Authors: Lakatamitou I , Middleton N , Paikousis L , Kouta C , Lambrinou E 
Published: October 2021

Abstract

Background
The Professional Quality of Life (ProQoL) scale is one of the most widely measures of compassion satisfaction and fatigue used, despite there is not much of published evidence to support its validity. The ProQoL scale assesses multiple domains of work experiences; compassion satisfaction, burnout and secondary traumatic stress. Our aim was to examine the psychometric properties of the Greek version of the ProQoL scale version 5 (Gr-ProQoL-5).

Method
A methodological study was contacted in order to assess the construct validity and reliability of the Gr-ProQoL-5. For that reason, 264 questionnaires were administrated by Greek-Cypriot healthcare professionals (HPs). Confirmatory factor analysis (CFA) and Exploratory factor analysis (EFA) were conducted to examine the relationship between the three Gr-ProQoL-5 dimensions (compassion satisfaction, burnout and secondary traumatic stress). Cronbach's a was calculated as well.

Results
CFA for Gr-ProQOL-5, did not confirm the initial scale's dimensions. In EFA five models were emerged. The models were then tested with CFA and after a panel discussion, the research team decided to keep one final model for the Gr-ProQoL-5. Items 1, 2, 4, 10, 15, 17 and 29 were eliminated from the analysis due to low communalities and multiple components loading. Three components were found representing compassion satisfaction, burnout and secondary traumatic stress.

Conclusions
The Gr-ProQoL-5 is an adequate instrument to assess ProQoL in Greek-Cypriot HPs and may be valuable for designing effective interventions to reduce burnout and compassion fatigue, and promote compassion satisfaction of HPs. More than ever and in the era of the pandemic the ProQoL seems to be a necessary quality indicator for health care systems.

Funding Acknowledgement
Type of funding sources: None.
Validity and reliability of a clinical non-exercise method for assessment of cardiorespiratory fitness using seismocardiography
Authors: Thunestvedt Hansen M , Roemer T , Hoejgaard A , Husted K , Soerensen K , Schmidt S , Dela F , Wulff Helge J 
Published: October 2021

Abstract

Introduction
Low cardiorespiratory fitness expressed as a low maximal oxygen consumption (V̇O2max) is associated with cardiovascular disease and all-cause mortality (1). Thus, V̇O2max is recognised as an important clinical tool in the assessment of patients (1,2). However, assessment of V̇O2max by exercise testing is both physically demanding and methodologically challenging and hence the clinical applicability is limited.

Purpose
Therefore, the aim of this study was to investigate the accuracy and precision of a clinical non-exercise method for assessment of V̇O2max.

Methods
On three separate days 20 healthy men (n=10) and women (n=10) with varying age (22–72 years) and fitness levels performed two tests for determination of V̇O2max; (a) a non-exercise test using seismocardiography (SCG V̇O2max) and (b) a graded exercise test to voluntary exhaustion on a cycle ergometer based on indirect calorimetry (IC V̇O2max). These tests were performed in order to examine the day-to-day reliability and the validity of SCG V̇O2max, respectively. Furthermore, SCG V̇O2max was assessed twice on each test day to investigate test-retest reliability. The SCG V̇O2max was performed in prone position following a short resting period by placing the SCG recording device on the xiphisternal joint with double adhesive tape. V̇O2max was assessed during a 5-minute recording of the sternal movement using SCG in combination with demographic data of the participants (3).
In addition, body composition was measured and a resting blood sample collected each test day.

Results
On average SCG V̇O2max was 3.3±2.4 ml/min/kg (mean ± 95% CI) lower than IC V̇O2max (p=0.013, SCG V̇O2max: 36.6±3.3 ml/min/kg, IC V̇O2max: 39.9±3.0 ml/min/kg). A significant positive correlation was found between SCG V̇O2max and IC V̇O2max (Pearson, r=0.72, p&lt;0.001). Both SCG V̇O2max and IC V̇O2max was similar between test days (p=0.972) and the intra-individual coefficient of variation was 4.5±2.9% and 4.0±2.5%, respectively.
Within each test day SCG V̇O2max was highly correlated (r=0.99, p&lt;0.0001) and no difference was observed between tests (p=0.993).

Conclusions
The accuracy of the current non-exercise assessment of cardiorespiratory fitness based on seismocardiography is not optimal as SCG V̇O2max was systematically lower than the gold standard assessment applying indirect calorimetry during a graded exercise test. Despite the abovementioned difference, SCG V̇O2max and IC V̇O2max were highly correlated. Furthermore, the precision of SCG V̇O2max is very high as both day-to-day and test-retest reliability were high.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): VentriJect ApS, Copenhagen, Denmark
Autophagy-related gene 5 (Atg5) is required for maintaining subcellular calcium homeostasis during acute cardiac stress
Authors: Djalinac N , Voglhuber J , Ljubojevic-Holzer S , Sedej S 
Published: October 2021

Abstract

Background
Autophagy exerts protective effects during cardiac stress inflicted by β-adrenergic stimulation and pressure overload. Contrarily, deletion of the cardiac-specific Atg5 gene contributes to left ventricular hypertrophy and contractile dysfunction, resulting in dilated cardiomyopathy. Heart failure is characterized by perturbations of excitation-contraction coupling (ECC) underlying alterations in intracellular calcium signaling.

Purpose
In this study, we aimed to understand whether loss of basal autophagy due to Atg5 deletion specifically in cardiomyocytes contributes directly to disturbances in subcellular calcium cycling.

Methods
Cardiac-specific Atg5−/− and Atg5+/+ mice were used to isolate ventricular cardiomyocytes, which were loaded with 8 μM Ca2+ indicator Fluo4/AM. Isolated cells were electrically stimulated and subjected to elevated workload by increasing pacing frequencies from 1 to 4 Hz. Cytosolic and nuclear calcium transients (CaTs) were recorded in line-scan mode using a laser scanning confocal microscope. Pharmacological inhibition of autophagic flux was performed by an intraperitoneal injection of 40 mg/kg leupeptin to Atg5+/+ mice.

Results
At baseline (1 Hz) stimulation the amplitude and kinetics of calcium transients were comparable between Atg5−/− and Atg5+/+ cells. However, after progressive increase of the pacing rate from 1 Hz to 4 Hz, Atg5−/− cardiomyocytes displayed reduced cytoplasmic and nuclear CaT amplitude, but increased nuclear time-averaged CaTs compared to controls. Such increase in nuclear calcium load stimulates Ca2+-dependent transcriptional activity, and likely involves CaMKII-mediated pro-hypertrophic gene program thus contributing to cardiac remodelling. In addition, we observed increased occurrence of arrhythmic events in Atg5−/− hearts at high pacing frequency, indicative of intracellular calcium overload and disturbed ECC. Acute pharmacological autophagy inhibition failed to elicit direct changes in time-averaged CaTs in the cytoplasm and nucleoplasm, suggesting that loss of Atg5-dependent autophagy seems to induce adverse cardiac remodelling that involves increased CaMKII activity due to the imbalances in nuclear Ca2+ levels.

Conclusion
Specific loss of ATG5 protein impairs calcium cycling during acute stress exposure by reducing CaT amplitudes, promoting arrhythmia, and increasing nuclear calcium load, which may induce hypertrophic gene expression. Further work is needed to identify key components mediating autophagy-related cardioprotection to develop strategies against cardiac remodeling and its progression to heart failure.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund (FWF)
Genesis of epicardial adipocytes and its association with progenitor markers, muscarinic receptor type 3 and b-blockers intake in patients with cardiovascular disease
Authors: Fu X , Almenglo C , Couselo-Seijas M , Fernandez A L , Martinez-Cereijo J M , Duran D , Gonzalez-Juanatey J R , Rodriguez-Manero M , Eiras S 
Published: October 2021

Abstract

Introduction
Epicardial fat thickness or volume was found to be associated with cardiovascular disease (CVD). Our aim was to study the epicardial adipocyte-progenitors' markers and its association with cholinergic or adrenergic activity in patients with cardiovascular disease.

Materials and methods
We have included epicardial adipose tissue (EAT) biopsies from 29 patients underwent open-heart surgery. From 10 patients (69±5 years old, 31±8 kg/ m2, 40% CAD, 40% HF, 60% AF, 0% T2DM) stromal cells from epicardial and subcutaneous fat were isolated after collagenase activity and cultured for 14 days and then submitted to adipogenesis for next 14 days. Samples from 19 patients (60±9 years old, 29±4 kg/m2, 42% CAD, 37% HF, 32% AF, 32% T2DM, 53% β-blockers) were used for “ex vivo assays”. Explants were split into equal pieces (100 mg), treated with or without acetylcholine (ACh) for 30 min. Afterwards RNA was isolated and cDNA was amplified by real time PCR. We selected adipocytes progenitors (CD36, PREF1, COL1A1), adipocytes markers (ADIPO, FABP4), muscarinic (muscarinic receptor type 2 (CHRM2) and 3 (CHRM2)) and β-adrenergic receptors (ABRD1, ABRD2 and ABRD3). Gene expression was represented regarding ACTB as 2HK/GEN.

Results
The stromal vascular cells (SVC) from subcutaneous fat (SAT) had higher expression levels of CD36, PREF1 and COL1A1 than SVC from epicardial fat (EAT). It explains the higher adipocytes markers after adipogenesis induction in SAT than EAT cells. However, an upregulation of fibroblasts markers was detected on EAT. The levels of CD36 and PREF1 in SVC were associated with higher adipogenesis. Although CHRM2 was higher in EAT than SAT SVC, the adipogenesis induction upregulated only CHRM3 (1.48±0.065 vs 1.42±0.036 a.u.) in EAT cells. Thus, this receptor was associated with adipocytes markers in epicardial fat (r=0.777 for CD36 and r=0.746 for FABP4) and incremented in epicardial fat biopsies from patients who were taken β-blockers (1.61±0.011 n=10 vs 1.54±0.097 a.u. n=9; p=0.05) and modulated by ACh treatment (p=0.05).

Conclusions
Our results showed that CD36 and PREF1 in epicardial SVC are adipocytes progenitors. The higher presence of adipocytes markers is associated with higher levels of muscarinic receptor (CHRM3), which are upregulated in epicardial fat from patients who were taken β-blockers and modulated by cholinergic activity. Because a metabolic and lipolytic dysfunction was associated with CHRM3, the sympathetic modulation might play a role in the epicardial adipocytes genesis. Further studies are needed to understand if this mechanism might improve or not future cardiovascular events.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ISCIII (PFIS2020)
Human pericardial fluid exosomes regulate macrophage immunophenotype: new prospective for cardiovascular myocardium-epicardium crosstalk in coronary artery disease
Authors: Ben-Aicha S , Anwar M , Behmoaras J , Punjabi P , Emanueli C 
Published: October 2021

Abstract

Background
The incidence and severity of ischemic heart disease (IHD) is exacerbated by coronary artery disease (CAD). Monocytes and macrophages are central to atherosclerosis. Endogenous small extracellular vesicles (sEVs) can shuttle microRNAs and other molecular cargos from cell to cell, mediating expressional and functional response in the recipient cells. Recent evidence supports a role for sEVs in modulating macrophage phenotype. The pericardial fluid (PF) is in direct contact with the epicardium and contain sEVs of myocardial origin (C. Beltrami et.al 2017). We recently showed that human PF-sEVs are capable to modulate cardiovascular cells via microRNA shuttling (C.Beltrami et.al. 2017). Moreover, epicardial cells reportedly cross-talk with the myocardium to regulate immune response to IHD (V.Ramjee et.al 2017).

Purpose
This study sought to investigate whether PF-sEVs regulate macrophages, contributing to a specific immunophenotypes in CAD patients.

Methods
PF was collected from either CAD patients undergoing coronary bypass surgery (CABG) or non-atherosclerotic patients operated for mitral valve repair (non-CAD control group). sEVs were isolated using size exclusion chromatography and characterised for size (Nanosight tracking analysis; NTA) and microRNA content (Exiqon miR-array). Monocytes from healthy donors were isolated from buffy coats and differentiated into macrophages following established protocols. Macrophages were incubated with either CAD-sEVs or non-CAD sEVs for 24h at 37oC. PBS and sEV-free serum were used as negative controls and LPS as a proinflammatory control. The cells were collected and processed for mRNA analyses (qRT-PCR) and Flow cytometry (FACS).

Results
Twenty-four-hour exposure to CAD-sEVs induces a proinflammatory profile of human macrophages. While non-CAD-sEVs did not statistically differ from PBS nor Exo-free groups, CAD-sEVs increased the mRNA level of IL1a, NOS3, TNFa, CCL2 and IL6 (comparison to both non-CAD and negative controls). These data were not associated with changes in apoptosis. Bioinformatics analysis showed that 11 miRNAs where consistently increased, and 67 miRNAs decreased in the PF-sEVs from all CAD patients compared to non-CAD. miRNA targets prediction and pathway analyses (R-Project) revealed that the deregulated miRNAs could regulate macrophage motility and cytokine signalling.

Conclusions
We demonstrate, for the first time, that sEVs isolated from the PF of CAD patients induce a proinflammatory profile of human macrophages. These clinically relevant results could drive to decipher improved therapeutics able to modulate the epicardial/myocardial immune response in CAD patients.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): Biritish Heart Fundation grant to Prof. Costanza Emanueli
Direct 3D printing of hiPSC-cardiomyocytes in collagen-based bioinks
Authors: Esser T U , Engel F B 
Published: October 2021

Abstract

Background
Cardiac tissue engineering is an effective strategy to generate tissues for drug testing and disease modelling as well as for cardiac repair. Tissues produced by casting show good functionality and advanced maturation, but do not replicate the native tissue architecture and hierarchy. Additive manufacturing technologies, such as 3D bioprinting, enable the generation of hierarchically structured tissues with complex geometries. This technology has been used previously to generate models of the heart. However, these approaches either showed limited tissue functionality or required a two-step procedure using a structural and a cell-laden bioink.

Purpose
Here, we aimed to develop a collagen-based bioink, which enables direct 3D-bioprinting of hiPSC-derived cardiomyocytes and supports the formation of functional cardiac tissue.

Methods
To generate cardiac tissues, a commercial pneumatic extrusion bioprinter with custom modifications to enable passive cooling of the bioink was used. Gelatin/gum arabic microparticles were obtained through complex coacervation, compacted by centrifugation and utilized as support bath. Cardiomyocytes were differentiated in 2D monolayer and expanded by CHIR99021-treatment and regular passaging. Cells were encapsulated in a rat collagen-I based bioink and printed into support bath prior to gelation. After bioink gelation at 37°C, support bath was removed, and constructs cultivated free-floating for up to 30 days.

Results
We printed ring-shaped cardiac tissues measuring 5 x 5 x 1 mm, which remained stable over the course of cultivation. First contractions were observed after three days, which increased in magnitude and synchronized across the tissue with prolonged culture. HiPSC-cardiomyocytes displayed striated sarcomeres and were responsive to pharmacological stimulation. In addition, using two distinct bioinks, multi-layered constructs were generated.

Conclusion
3D-bioprinting is a promising tool to generate engineered cardiac tissues with complex geometries and improved functionality through designed hierarchy. Our collagen-based bioink and associated printing strategy enables the fabrication of Collagen-based contractile cardiac tissues in a direct manner.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG) Contractions of printed cardiac tissue
MicroRNA let-7a, -7e and -133a attenuate hypoxia-induced atrial fibrosis via targeting collagen expression and the JNK pathway in HL1 cardiomyocytes
Authors: Lo C H , Yang S F , Li L C , Ueng K C 
Published: October 2021

Abstract

Background
Atrial fibrillation (AF) is becoming an enormous public health challenge, and it is associated with major cardiovascular morbidity and mortality. There is a need for a better understanding of the causes and consequences of the hypoxia-related development of AF and atrial remodeling. Fibrosis is a hallmark of atrial structural remodeling. Micro-ribonucleic acids (miRNAs) have been reported to have an impact on the pathogenesis of cardiac diseases. Evidence that specific miRNAs can influence AF related to atrial structural remodeling and fibrosis via the modulation of collagens under myocardial hypoxic conditions is lacking. The aim of this study was to investigate the role of miRNAs in the modulation of fibrotic molecular mechanisms in response to hypoxic conditions, which may mediate atrial fibrosis.

Methods
Hypoxia was induced by cobalt chloride and hypoxia chamber respectively. MiRNA arrays were used to identify the specific miRNAs associated with the modulation of fibrotic genes. Luciferase assay, real-time polymerase chain reaction, immunofluorescence and Western blotting were used to investigate the effects of miRNAs on the expressions of the fibrotic markers collagen I and III (COL1A, COL3A) and phosphorylation levels of the stress kinase c-Jun N-terminal kinase (JNK) pathway in cultured HL-1 atrial cardiomyocytes cell line.

Results
COL1A and COL3A were found to be the direct regulatory targets of miR-let-7a, miR-let-7e and miR-133a in hypoxic atrial cardiac cells in vitro. The expressions of COL1A and COL3A were influenced by treatment with miRNA mimic and antagomir. The delivery of miR-133a, miR-let-7a or miR-let-7e inhibited hypoxia-induced collagen expression. The JNK pathway was critical in the pathogenesis of atrial fibrosis. Inhibition of JNK phosphorylation (JNK inhibitor SP600125) could be able to increase expression of miRNAs and repressed the fibrotic markers COL1A and COL3A which in turn might reduce the arrhythmogenic atrial remodeling. This study highlights the important role of miRNA in hypoxia-related atrial remodeling as well as atrial fibrosis.

Conclusion
MiRNA let-7a, miR-let-7e and miR-133a play important roles in hypoxia-related atrial fibrosis by inhibiting collagen expression and post-transcriptional repression by the JNK pathway. These novel findings may lead to the development of new therapeutic strategies.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the grants from the Ministry of Science and Technology (MOST), Taiwan, ROC Regulation of cardiac fibrosisRegulation of collagen types by miRNAs