bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mid-term endothelial dysfunction post COVID-19
Authors: Lampsas S , Oikonomou E , Siasos G , Souvaliotis N , Goliopoulou A , Mistakidi C V , Theofilis P , Vogiatzi G , Kalogeras K , Katsianos E , Tousoulis D , Vavuranakis M 
Published: October 2021

Abstract

Introduction
Cardiovascular complications of Coronavirus disease (COVID-19), resulting from the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), have been documented. Endothelium-induced “cytokine storm” in critically ill COVID-19 patients is one of the leading causes of morbidity and mortality. Vascular endothelial damage caused by COVID-19 emphasizes the crucial role of endothelium in COVID-19 clinical impact.

Purpose
To examine the mid-term (1-month) impact of COVID-19 in endothelial function.

Methods
In this case control study, 20 consecutive patients who were hospitalized for COVID-19 either on Intensive Care Unit (ICU) or non-ICU were examined one month following hospital discharge. In the control group we recruited 12 consecutive subjects from the outpatient cardiology clinic. Demographic and clinical data were collected, and endothelial function was evaluated by brachial artery flow-mediated dilation (FMD).

Results
There was no difference in age between COVID-19 patients and control subjects (66±12 years vs. 71±5 years, p&lt;0.17), in male sex (63% vs. 54%, p=0.66) in history of diabetes mellitus (27% vs. 36%, p=0.64), hypertension (36% vs. 54%, p=0.39), cardiovascular disease (27% vs.18%, p=0.61). From the COVID-19 subjects 65% were overweight or obese. During their hospitalization [3 ICU (15%)/17 non-ICU (85%), mean days: 17±6.7], 4 (20%) of COVID-19 patients developed ARDS, while single cases of stress-induced cardiomyopathy, pulmonary embolism, and acute coronary syndrome were detected. One month post discharge D-dimers (0.71±0.55 μg/ml) levels were above upper reference limit. Importantly, FMD one month after hospital discharge date, was significantly impaired in the COVID-19 group (3.59±1.63% vs. 9.31±2.98%, p&lt;0.001) compared to control group.

Conclusion
Post COVID-19 subjects one month post discharge have significant impaired endothelial function compared to control subjects. These findings highlight the significant interaction of COVID-19 with arterial endothelium and merit further research to conclude on the exact impact of vascular endothelium in physical history of SARS-CoV-2 infection.

Funding Acknowledgement
Type of funding sources: None.
A multivariate analysis identifies genetic loci associated with atherosclerotic plaque composition and cardiovascular disease trajectory
Authors: Cui K , Mekke J , Haitjema S , Pasterkamp G , Asselbergs F W , Mokry M , Van Der Laan S W 
Published: October 2021

Abstract

Background
From cross-sectional studies we have learned that composition of atherosclerotic plaques differs between individuals, and this contributes to the inter-individual differences in susceptibility to incident coronary and cerebral events. In pathological studies the extent and type of atherosclerosis is commonly assessed based on histological plaque characteristics that are linked to plaque rupture and erosion. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases.

Objectives
We investigated the genetics of the plaque through multivariate and integrative genome-wide analyses (GWAS) of individual plaque characteristics.

Methods
We included carotid endarterectomy patients from the Athero-Express Biobank Study (n=2,124) with high-density imputed data and extensive histochemical plaque phenotyping available. We used slideToolKit to quantify the number of endothelial cells, macrophages and smooth muscle cells (SMCs), and manually assessed the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. We ran GWAS on all traits correcting for age, sex, array used, and genetic ancestry.

Results
We identified 3 loci that significantly associate with CD68+ macrophages and ACTA2+ SMCs, p&lt;5x10–8. Statistical finemapping revealed 9 variants in the 95% credible set and functional annotation linked these to genes associated with malignant neoplasms, circulating cholesterol, and transmembrane proteins, suggesting an effect on cellular proliferation and cholesterol metabolism.

Conclusions
We provide evidence for 3 loci that modulate plaque composition through macrophages and smooth muscle cell plaque proliferation and cell-cell interactions.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): European Research Area Network on Cardiovascular Diseases (ERA-CVD, druggable-MI-genes),China Scholarship Council
Protective effects of dapagliflozin on vascular remodeling in the carotid artery following balloon injury – potential role of angiotensin and purinergic signaling
Authors: Matsushita K , Sato C , Bruckert C , Gong D , Hmadeh S , Fakih W , Remila L , Auger C , Jesel L , Ohlmann P , Kauffenstein G , Schini-Kerth V , Morel O 
Published: October 2021

Abstract

Introduction
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. The possibility that SGLT2 inhibitors improve endothelial regeneration and vascular restenosis is unknown.

Purpose
To examine whether dapagliflozin, a selective SGLT2 inhibitor, could prevent neointima thickening induced by balloon injury and, if so, to determine the underlying mechanisms. The effect of dapagliflozin was compared to that of losartan, an angiotensin type 1 receptor (AT1R) antagonist.

Methods
Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) were administered orally for 5 weeks to male Wistar rats. Balloon injury of the left carotid artery was performed 1 week after starting the treatment and sacrificed 4 weeks later. Vascular reactivity was assessed on left (injured) and right (healthy) carotid artery rings. The extent of neointima was assessed by histomorphometric analysis, changes of target factors by immunofluorescence, RT-qPCR and histochemistry.

Results
Dapagliflozin and losartan treatments reduced neointima thickening by 32% and 27%, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured artery. These effects were not modified by the dapagliflozin or the losartan treatments. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, ITGAM, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers and a decreased of eNOS in the injured carotid. However, these changes were not affected by the pharmacological treatments. By contrast, significant increased levels of AT1R angiotensin receptor and NTPDase1 (CD39) ectonucleotidase were observed in the restenotic carotid artery of the dapagliflozin group. Histochemical analysis evidenced important NTPDase1 activity in the neointima.

Conclusions
Dapagliflozin effectively reduced neointimal thickening. As the contribution of AT1R and P2Y2 ATP receptor in smooth muscle cell proliferation and neointima formation has been reported in the literature, the present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 transporter represent potential new target for limiting vascular restenosis.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): This work was supported by AstraZeneca
PI 3-kinase isoform PI3Kalpha controls smooth muscle cell functionality and protects against aortic aneurysm formation
Authors: Vantler M , Schorscher M , Berghausen E , Zierden M , Wissmueller M , Mollenhauer M , Mehrkens D , Adam M , Baldus S , Rosenkranz S 
Published: October 2021

Abstract

Background
Class I PI 3-kinase isoform PI3Kα is a lipid kinase and signals downstream of receptor tyrosine kinases. Smooth muscle cells (SMCs) lacking PI3Kα are characterized by impaired proliferation, migration and survival. Mice, harbouring a smooth muscle specific PI3Kα deficiency (SM-PI3Kα−/−), display reduced vascular wall thickness and impaired vascular remodeling in response to vessel injury. We hypothesize that SM-PI3Kα−/− mice are prone to aortic aneurysm (AA) formation due to impaired SMC functions. Herein, we investigated, how PI3Kα-dependent signaling in SMCs affect aortic aneurysm (AA) formation, aortic wall structure, and expression of extracellular matrix (ECM) components.

Methods and results
AA formation in SM-PI3Kα−/− mice and wild-type littermates was examined by means of the “porcine pancreatic elastase” (PPE) AA model. PPE was infused into the infrarenal aorta to induce AA formation. Ultrasound examination revealed a significantly increased aortic diameter in SM-PI3Kα−/− mice (1.22±0.12 mm) compared to wild-type animals (0.96±0.02 mm, p=0.014). These data indicate a protective function of SM-PI3Kα in AA formation. In addition, the media thickness in the abdominal aorta was significantly reduced in SM-PI3Kα−/− mice (29.0±3.1 vs. 42.5±4.1 μm). Ultrastructural analysis of aortic wall morphology in SM-PI3Kα−/−mice using transmission electron microscopy (TEM) showed a deranged tunica media with detached SMCs and increased apoptotic cell death. Consequently, SM-PI3Kα deficiency significantly diminished responsiveness of aortic rings to vasodilator acetylcholine and NO-donor nitroglycerin, further indicating impaired aortic wall structure. Western blots demonstrated a reduced elastin and fibrillin expression in SMCs from SM-PI3Kα−/− mice. Furthermore, immunofluorescence stainings of PI3Kα−/− and wild-type SMCs, cultured for seven days under 10% fetal calf serum containing DMEM medium, showed significantly disturbed structures of elastin-, fibrillin-1- and collagen-1-fibers. These data indicate that PI3Kα signaling contributes to elastic fiber homeostasis thus affecting SMC phenotypic modulation. Immunoblots demonstrated that PDGF and insulin induced phosphorylation and inactivation of key regulators of SMC differentiation and dedifferentiation including FoxO1, FoxO3a, Foxo4, and GSK3b, respectively, were reduced or even abrogated in PI3Kα−/− SMCs.

Conclusion
These data show that deficiency of PI3Kα in SMCs promotes the formation and progression of AA. Causative is a deranged aortic structure of SM-PI3Kα−/− aortae which can likely be attributed to an impaired production of elastic fiber components by PI3Kα−/− SMCs.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft
The m6A methyltransferase METTL3 promotes hypoxic pulmonary arterial hypertension via targeting PTEN
Authors: Yuhan Q I N , Chengchun T A N G 
Published: October 2021

Abstract

Background
N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammal mRNAs. Accumulating evidence has indicated the crucial role of m6A modification in cardiovascular diseases including cardiac hypertrophy, heart failure, ischemic heart disease, vascular calcification, restenosis, and aortic aneurysm. However, the role of m6A methylation in the occurrence and development of hypoxic pulmonary hypertension (HPH) remains largely unknown.

Purpose
The present study aims to explore the role of key transferase METTL3, in the development of HPH.

Methods
Hypoxic rat models and pulmonary artery smooth muscle cells (PASMCs) and were used to research the METTL3-mediated m6A in HPH in vivo and in vitro. CCK-8, EdU, PCNA, transwell and TUNEL assay were performed to evaluate the proliferation, migration and apoptosis rates of PASMCs. m6A RNA Methylation Quantification Kit and m6A-qPCR were utilized to measure the total m6A level and m6A-PTEN mRNA expression. RNA immunoprecipitation and RNA pull down were used to detect the interaction between METTL3 and PTEN mRNA. The half-life of mRNA was detected through actinomycin D assay.

Results
Both METTL3 mRNA and protein were found abnormally upregulated in pulmonary arteries of HPH rats and hypoxia induced PASMCs. Furthermore, downregulation of METTL3 attenuated PASMCs proliferation and migration exposed to hypoxia. In addition, m6A binding protein YTHDF2 was found significantly increased in HPH group in vivo and in vitro. Mechanistically, YTHDF2 recognized METTL3 mediated m6A-PTEN mRNA and promoted the degradation of PTEN. Decreased PTEN led to over-proliferation of PASMCs through activation of PI3K/Akt signaling pathway.

Conclusion
METTL3/YTHDF2/PTEN axis exerts a significant role in hypoxia induced PASMCs proliferation, providing a novel therapeutic target for HPH.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): National Natural Science Foundation of China Figure 1
Parathyroid hormone affects right heart hemodynamics and exacerbates pulmonary hypertension
Authors: Joki Y J , Konishi H K , Takasu K T , Minamino T M 
Published: October 2021

Abstract

Background
Pulmonary hypertension (PH) is characterized by increased pulmonary artery pressure and develops right heart failure. Parathyroid hormone (PTH) is secreted from parathyroid gland and regulates a calcium homeostasis. Recent studies have suggested that PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We hypothesized that PTH would play a role in the pathogenesis of PH.

Purpose
This study aimed to investigate the effect of PTH on pulmonary hemodynamics.

Method
We measured serum PTH levels in patients who were suspected of PH and underwent right heart catheter examination. We used two types of PH animal models, hypoxia (Hx)-induced PH mouse model and Sugen/hypoxia (SuHx)-induced PH rat model. Hx mice were administered PTH daily for 3 weeks. SuHx rats underwent parathyroidectomy, after which they received SuHx treatment for 10weeks. We measured physical data and right ventricular systolic pressure (RVSP) in these models. We cultured pulmonary artery smooth muscle cell (PASMC) treated with PTH to analyze cell signaling, proliferation and migration.

Result
We enrolled 20 participants. PTH concentration was significantly correlated with mean pulmonary artery pressure (r=0.58, p=0.006) as well as with pulmonary vascular resistance (r=0.61, p=0.04). Receiver operating characteristic curve displayed a cut-off PTH level of 48.0pg/ml that offered optimal differentiation between patients with and without PH (100% sensitivity, 73% specificity). PTH treatment exacerbated right ventricular hypertrophy and increased RVSP (33.6mmHg vs. 48.2mmHg) in Hx mice compared with non-treated Hx mice (Figure 1). Conversely, parathyroidectomy significantly attenuated right ventricular hypertrophy and reduced RVSP (54.2mmHg vs. 29.3mmHg) in SuHx rats compared with sham-operated SuHx rats. PTH promoted migration and proliferation through ERK signaling in PASMC.

Conclusion
Our clinical and experimental data demonstrated a critical role of PTH in the development of PH and suggested that PTH would be a novel therapeutic target for PH treatment.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Young Scientists Figure 1. PTH treatment exacerbated RVSP
Senescent endothelial cells exacerbate pulmonary hypertension through notch-mediated juxtacrine interaction with pulmonary artery smooth muscle cells
Authors: Ramadhiani R , Ikeda K , Miyagawa K , Ryanto G R T , Tamada N , Suzuki Y , Hirata K , Emoto N 
Published: October 2021

Abstract

Background
Despite recently developed clinical therapies, vascular remodelling in pulmonary arterial hypertension (PAH) progressively worsen. Hemodynamic unloading has been proposed to normalize the remodelled pulmonary vascular structures in the lungs. Recently, it has been reported that cellular senescence was associated with the irreversibility of pulmonary vascular structures after hemodynamic unloading.

Purpose
This study aims to elucidate the role of senescent endothelial cells (ECs) in the pathogenesis of PAH.

Methods
We generated EC-specific progeroid mice in which ECs undergo premature senescence by overexpressing the dominant-negative form of telomere repeat-binding factor 2 under the control of the VE-cadherin promoter. Following three weeks of hypoxia exposure, the PH phenotypes were assessed by RVSP, lung histology, and RT-qPCR. The interaction of human pulmonary artery ECs (hPAECs) and human pulmonary artery smooth muscle cells (hPASMCs) was indirectly and directly explored through the co-culture system. Gamma-secretase inhibitor (DAPT) was administrated to inhibit Notch signalling both in the in-vitro and in-vivo study.

Results
EC-specific progeroid mice showed exacerbated pulmonary hypertension after chronic hypoxia exposure, accompanied by the enhanced medial SMCs proliferation in the distal pulmonary arteries. Contact-mediated interaction with senescent hPAECs increased proliferation and migration capacities in hPASMCs, while no such effects were detected in the absence of ECs-SMCs contact. Consistently, senescent ECs highly expressed Notch ligands, thus activated Notch signalling in hPASMCs, leading to increased Notch target genes in hPASMCs. Pharmacological inhibition of Notch signalling attenuated the enhanced SMCs proliferation and migration induced by senescent hPAECs, as well as the worsened PH phenotypes in EC-specific progeroid mice.

Conclusions
Our data established a crucial role of senescent ECs in the PAH pathogenesis through the dysregulated SMC functions via juxtacrine signaling. Senescent ECs are attracting targets for further pathological-targeted therapy to cure PAH completely.

Funding Acknowledgement
Type of funding sources: None.
Efficacy and safety of direct oral anticoagulants in morbidly obese patients with non-valvular atrial fibrillation: a systematic review and meta-analysis
Authors: Mhanna M , Beran A , Al-Abdouh A , Srour O , Abdulsattar W , Srour O , Altujjar M , Alom M , Abumoawad A , Assaly R 
Published: October 2021

Abstract

Introduction
Atrial fibrillation (AF) is the most common arrhythmia, with an estimated prevalence between 1–4%. On the other hand, obesity continued to be a prevalent health issue worldwide. Direct oral anticoagulants (DOACs) have been increasingly preferred over warfarin; however, The International Society of Thrombosis and Hemostasis (ISTH) recommended avoiding the use of DOACs in patients with a BMI &gt;40 or weight &gt;120 kg because of limited clinical data in these patients. In this meta-analysis, we aimed to evaluate the efficacy and safety of DOACs in morbidly obese patients with non-valvular AF.

Method
We performed a comprehensive literature search using multiple databases from database inception through January 2021, for all the studies that evaluated the efficacy and safety of DOACs in morbidly obese patients with non-valvular AF. The primary outcome of interest was stroke or systemic embolism (SSE) rate. The secondary outcome was major bleeding (MB). All meta-analyses were conducted using a random-effect model.

Results
A total of 10 studies including 89,494 morbidly obese patients (BMI &gt;40 or weight &gt;120 kg) with non-valvular AF on oral anticoagulation therapy (45427 on DOACs vs. 44067 on warfarin) were included in the final analysis. One included study was a randomized controlled trial (RCT), another study was a post hoc analysis of an RCT and the rest were retrospective cohort studies. The mean follow-up period was 1.8 years (range 8 months to 3.1 years). The SSE rate was significantly lower in DOACs group compared to warfarin group (odds ratio (OR): 0.71; 95% confidence interval (CI): 0.62, 0.81; p&lt;0.0001; I2=0%). MB rate was also significantly lower in DOACs group compared to the warfarin group (OR 0.60, 95% CI 0.46–0.78, P&lt;0.0001, I2=86%). Subgroup analysis in the rivaroxaban and apixaban AF cohort showed a statistically significant difference in SSE and MB event rates favoring both over warfarin therapy. Dabigatran showed non-inferiority to warfarin in SSE rate but superiority in the safety outcome.

Conclusions
Our meta-analysis demonstrated that DOACs are effective and safe when compared to warfarin in morbidly obese patients. However, more large scale randomized clinical trials are needed to further evaluate the efficacy and safety of DOACs compared to warfarin in this cohort of patients.

Funding Acknowledgement
Type of funding sources: None. Stroke and systemic embolism eventsMajor bleeding events
URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and BAT whitening in mice
Authors: Tanaka Y , Nagoshi T , Yoshii A , Oi Y , Takahashi H , Kimura H , Kashiwagi Y , Tanaka T D , Yoshimura M 
Published: October 2021

Abstract

Background
Accumulating evidence suggests that high uric acid is strongly associated with obesity and metabolic syndrome and drives the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidney, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear.

Objectives
We hypothesizes that URAT1 plays an important role in obesity-induced metabolic disorders, and URAT1-selective inhibitor treatment ameliorates systemic insulin resistance, NAFLD and adipose tissue dysfunction using diet-induced obese mice.

Methods
Mice fed a high-fat diet (HFD) for 16 to 18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks.

Results
Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than kidney. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis, as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (Ccl2 and TNFα), all of which were attenuated by dotinurad. Likewise, HFD significantly increased URAT1 expression in BAT, resulting in the lipid accumulation (whitening of BAT) and increased production of tissue reactive oxygen species, which were reduced by dotinurad via UCP1 activation.

Conclusions
A novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome, and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.

Funding Acknowledgement
Type of funding sources: None.