bluuebunny/crossref_metadata_2025_split huggingface dataset:
Micromanaging atherosclerosis: myeloid cell-specific microRNA-26b attenuates atherosclerosis development
Authors: Peters L , Bidzhekov K , Jansen Y , Bayasgalan S , Gencer S , Sundararaman SS , Bonnin-Marquez A , Yan Y , Jans AM , Bartneck M , Doering Y , Weber C , Van Der Vorst E 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.
Increasing evidence has shown that microRNAs (miRs) are fundamental players in atherosclerosis, but the exact role of various miRs remains elusive. Preliminary data showed that, with a 5-fold increase, miR-26b was the most highly expressed miR in human atherosclerotic plaques compared to healthy vessels. Therefore, we aimed to determine its cell-specific effects on atherosclerosis development.
We examined the role of miR-26b in atherosclerosis by using full-body knockout (KO) mice on a 4 weeks and 12 weeks Western type diet (WTD) and myeloid cell-specific miR-26b KO (LysM-Cre) mice on 12 weeks WTD on an apolipoprotein E-deficient background. Atherosclerotic plaque size and phenotype were analyzed via immunohistochemical and immunofluorescent stainings. The phenotype and function of bone marrow-derived macrophages (BMDMs) from full body KO mice were analyzed via PCR, ELISA and gelatinase assays. Lipid nanoparticles (LNPs) served as vehicles for miR-26b mimics to restore miR-26b levels in knockout BMDMs.
A full-body miR-26b-KO on a 12 weeks WTD resulted in a striking 3.5-fold increase in atherosclerotic lesion size, compared to control. Consistent with a more advanced plaque phenotype, collagen content, smooth muscle cell percentage and relative necrotic core area were all significantly increased in plaques from miR-26b KO mice whilst the relative macrophage content was significantly reduced. Interestingly, the full-body KO mice on a 4 weeks WTD showed a remarkable 10-fold increase in plaque size and the respective plaques also had a reduced macrophage percentage, showing that miR-26b has very strong effects on both atherogenesis as well as atherosclerosis progression. Intriguingly, relative plaque size in the arches of miR-26b LysM-Cre mice were increased by 3-fold and collagen content was also increased significantly, suggesting a role for myeloid-specific miR-26b in atherosclerosis development. Further highlighting its myeloid-specific effects, miR-26b KO BMDMs showed an increase in IL-6 and TNFα secretion, which could be rescued by LNPs containing miR-26b mimics. Additionally, these miR-26b KO BMDMs showed a reduction in collagen breakdown.
Overall, our results clearly demonstrate an atheroprotective role of myeloid cell-specific miR-26b by attenuating lesion initiation as well as progression, mainly by suppressing inflammation and stimulating collagen breakdown. Our study leads to exciting new insights into the role of miR-26b in atherosclerosis development, providing an important back-bone for future research and potential new treatment options.
MiR-6821-5p and coronary calcification in familial hypercholesterolemia patients with subclinical atherosclerosis
Authors: Padro T , Escate R , Suades R , Mata P , Badimon L 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Agencia Estatal de Investigaciópn (AEI)” - Spanish Ministry of Economy Competitiveness of Science Agencia Estatal de Investigaciópn (AEI)” - Spanish Institute of Health Carlos III, ISCIII

Background
Familial hypercholesterolemia (FH) is associated with premature atherosclerosis but FH patients have a highly variable risk of clinical atherosclerotic cardiovascular disease (ACVD) presentation. Preclinical atherosclerosis has been identified by imaging of coronary artery calcium (CAC); however, little is known of the molecular pathways involved in vascular calcification in FH. Circulating microRNAs are proven as a powerful epigenetic regulators of atherosclerosis development.

Purpose
We have investigated the circulating microRNA signature of FH patients with CAC and asymptomatic atherosclerosis.

Methods
Differential plasma miRNA profiling was performed by Affymetrix microarray technology (discovery studies) and RT-PCR using TaqMan technology (validation studies) in plasma of FH subjects (N=86) included in a multicentric nationwide cohort. FH-patients with and without coronary calcification (determined by Agatston score) by computed tomographic angiography imaging were investigated. Proof-of-concept validation studies were performed in cell culture of human coronary-derived vascular smooth muscle cells (hcVSMC) calcification analysis.

Results
Using a non-targeted approach, a differential signature of 15 miRNA (all upregulated) was identified in FH-patients presenting subclinical atherosclerosis with calcified plaques (FH-CCS+, N=49, Agatston score &gt;100) compared with FH-subjects without coronary calcification (FH-CCS-, N=37, Agatston score 0). After RT-PCR validation, 3 miRNAs (miR-193a-5p, miR-30e-5p and miR-6821-5p) were significantly upregulated in FH-CCS+ patients. ROC-analysis confirmed miR-6821-5p as the best miRNA for discriminating FH-patients with coronary calcification (AUC 0.70±0.06, P=0.003). High miR-6821-5p levels associated to older age (P=0.003) and high LDL burden (P=0.014), two established risk factors for calcification. In vitro studies showed miR-6821-5p up-regulation (P=0.018) in hcVSMC cultured under calcification conditions (high-phosphate medium) and expressing increased levels of calcification-related genes such as SPP1 (Secreted Phosphoprotein 1, osteopontin) and BMP2 (Bone Morphogenetic Protein 2) when compared with non-calcified hcVSMC.

Conclusion
Up-regulated levels of miR-6821-5p are found in FH patient with CAC+ atherosclerotic plaques, as well as in calcified isolated human coronary smooth muscle cells that express the pro-calcification genes as osteopontin and BMP2. miR-6821-5p is involved in the development of calcification in the coronary arteries and in the development of atherosclerotic plaques.
Beneficial impact of pork dry-cured ham consumption on blood pressure and cardiometabolic markers in individuals with high cardiovascular risk
Authors: Montoro-Garcia S , Velasco-Soria A , Abellan-Aleman J 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundación Séneca de la Región de Murcia through the project “Jovenes Líderes en Investigación" RETOS-COLABORACIÓN (Ministerio de Ciencia y Tecnología.

Background
Evidence suggests that bioactive-peptides reduce hypertension and affect certain metabolic pathways.

Methods
Fifty-four volunteers with stage 1-hypertension and/or hypercholesterolemia and/or basal glucose &gt;100 mg/dL were recruited and randomized to particular pork dry-cured ham (treatment) and cooked-ham (placebo) products for 2.5 months. Bioactive-peptides composition and enzyme inhibitory activities of both particular meat products were characterized. Treatment comparisons for the main effects were made using a 2 (treatment) × 2 (times) repeated measures minus the effect of cooked-ham.

Results
24h mean systolic and diastolic pressures decreased up to 2.4 mmHg in the dry-cured ham period (p=0.0382 y p=0.0233, respectively) as well as the number of systolic pressure measures &gt; 135 mmHg (p=0.0070). Total cholesterol levels also decreased significantly after dry-cured ham intake (p=0.049). No significant differences were observed between the two treatments for basal glucose, HOMA-IR index and insulin levels (p&gt;0.05). However, significant rise of ghrelin level was observed, while leptin plasma values slightly decreased (treatment effect, p=0.0350 and p=0.0528, respectively).

Conclusions
This study suggested the beneficial effects of regular bioactive-peptides consumption on the improvement of systolic/diastolic blood pressures and emphasized the potentially regulation of ghrelin/leptin levels which provides new therapeutic opportunities for metabolic disorders in the cardiovascular primary prevention.
Does targeted temperature management increase the risk of stent thrombosis in survivors of out-of-hospital cardiac arrest? A single centre experience
Authors: Kanji R , Gue YX , Saw AM , Shahid MQ , Gorog DA 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Introduction
Acute Myocardial Infarction (AMI) complicated by out-of-hospital cardiac arrest (OCHA) carries a poor prognosis. Emergent angiography and primary percutaneous coronary intervention (PPCI) has been shown to improve survival, however some patients are left with significant neurological sequelae. Targeted Temperature Management (TTM) in randomised controlled trials has improved neurological status in survivors, however concerns have arisen from case series demonstrating a higher incidence of stent thrombosis. Reduced absorption of orally-administered P2Y12 inhibitor medication has been demonstrated in this cohort on the intensive care unit (ICU) and has been proposed to account for an observed increase in stent thrombosis.

Purpose
Our aim was to assess the relationship between stent thrombosis and TTM in patients with OHCA due to AMI and undergoing primary percutaneous coronary intervention (PPCI).

Methods
We conducted a single centre, retrospective analysis of consecutive patients admitted to the East and North Hertfordshire NHS Trust with an OHCA secondary to ST-elevation myocardial infarction and treated with PPCI. All patients received aspirin loading and either enteral P2Y12 inhibitor loading (ticagrelor or clopidogrel) or intravenous (cangrelor) prior to or immediately after PPCI, according to clinician preference. Glycoprotein IIb/IIIa administration was determined by physician choice and documented. All patients were transferred to the ICU straight after PPCI, where some received TTM. Notes were reviewed to allow recording of demographic and procedural data, including post resuscitation care up to hospital discharge.

Results
A total of 92 patients were identified, 80% male and aged 62 +/-12.5 years. In addition to aspirin, patients were treated with P2Y12 inhibitors with 72.5% loaded with ticagrelor, 2.5% with clopidogrel and the remaining 25% with intravenous cangrelor. In addition, 49% of patients received periprocedural glycoprotein IIb/IIIa inhibitor.
TTM was initiated in 38 patients (41%) using surface pads. The average duration of TTM was 24 hours. No cases of stent thrombosis occurred. In-hospital all-cause mortality was 24%. The death rate was higher amongst those patients who were cooled, but this difference was not statistically significant (35% vs 17%, p = 0.08). Cangrelor use was significantly higher in the cooled cohort (43% vs. 8%, p &lt; 0.001), but glycoprotein IIb/IIIa inhibitor use was similar between those receiving and not receiving TTM (38% vs. 57%, p = 0.088).

Conclusion
No definite stent thromboses were recorded in the 92 patients reviewed, suggesting that TTM does not increase the risk of stent thrombosis. Our conclusion is limited by the small sample size, and the heterogeneity in P2Y12 inhibitor use, particularly the higher use of cangrelor in the cooled cohort.
Ursolic acid reduces inflammation and fibrosis in the kidney of diabetic mice
Authors: Manea SA , Lazar AG , Vlad ML , Manea A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UEFISCDI

Background
Diabetic kidney disease (DKD) is arguably the major disabling and life-threatening microvascular-related disorder associated with both type I and type II diabetes. Inflammation of glomerular capillary system and progressive accumulation of glomerular extracellular proteins are important culprit mechanisms leading to glomerulosclerosis and ultimately renal failure in end-stage DKD. Conventional anti-diabetic therapies can only delay the progression of DKD. The naturally-occurring triterpenic acids emerged as important candidate pharmacological compounds for the treatment of cardiometabolic disorders.

Purpose
We aimed at investigating the potential regulatory effects of ursolic acid, a pentacyclic triterpenoid, on the expression of key pro-inflammatory and pro-fibrotic mediators in diabetic kidney.

Methods
Non-diabetic and streptozotocin-induced diabetic C57BL/6J male mice were randomized to receive via intraperitoneal injection 1 mg/kg ursolic acid (UA), or its vehicle (5% DMSO + 95% PBS, pH 7.4), for 4 weeks. Human endothelial cells (EC) were exposed to normal (5 mM) or high (25mM) concentration of glucose in the absence/presence of 1-10 μM UA. Real-time PCR, Western blot, and immunofluorescence microscopy techniques were employed to investigate the expression of selected DKD-relevant pro-inflammatory and pro-fibrotic molecules. Morphological aspects of the kidney and glomeruli were assessed by histochemistry.

Results
The mRNA/protein levels of pro-inflammatory (MCP-1, TNFα, NOS2, ICAM-1, VCAM-1, E-selectin) and pro-fibrotic (collagen IV, fibronectin, laminin, TGFβ) mediators were found significantly elevated in the kidney of diabetic mice as compared to non-diabetic counterparts. Treatment of diabetic mice with UA significantly reduced the up-regulated expression of pro-inflammatory mediators, extracellular matrix proteins, and pro-fibrotic factor TGFβ. Moreover, glomerular hypertrophy and the up-regulation of glomerular collagen IV, fibronectin, and laminin protein levels were significantly reduced in UA-treated diabetic mice. In cultured human EC, UA suppressed the high glucose-induced up-regulation of ICAM-1, VCAM-1, E-selectin and NF-kB signaling.

Conclusion
In experimental diabetes, ursolic acid down-regulates the expression of DKD-relevant pro-inflammatory and pro-fibrotic molecules in the kidney of diabetic mice by potentially targeting NF-kB signaling pathway. The data of this study suggest that triterpenic acids and their chemical derivates could become important pharmacological tools to reduce inflammation and fibrosis associated with DKD.
B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice
Authors: De Mol J , Postel R , Smit V , Bernabe Kleijn MNA , Bot I , Kuiper J , Foks AC 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation
ERA CVD

Aims
Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition, aging is related to an increased incidence of inflammatory diseases, such as the lipid-driven chronic inflammatory disease atherosclerosis, the main underlying cause of cardiovascular disease (2). B cells play a major role in atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets, with either proatherogenic or antiatherogenic properties, have been identified in atherosclerosis, but the impact of aging on B cells during atherosclerosis remains to be elucidated. In contrast to young atherosclerotic mice where few B cells are found within the plaque, single cell RNA sequencing and flow cytometry data from our group revealed that B cells are one of the most dominant leukocytes present in atherosclerotic aortas from naturally aged LDLr-/- mice. In this study, we aimed to gain further insights into the role of these aged B cells on T cell immunity in atherosclerosis by depleting B cells in aged atherosclerotic mice.

Methods and Results
Aged (85-95 weeks) atherosclerotic male LDLr-/- mice were kept on a chow diet for six weeks, during which the mice received 250 µg B cell-depleting anti-CD20 antibody (Genentech) (n=12) or 250 µg rat IgG2a isotype control (n=12) once a week intraperitoneally. Mice that received the anti-CD20 antibody showed effective B cell depletion in the blood and lymphoid organs, such as the spleen and lymph nodes, but also locally in the atherosclerotic plaque. In addition, B cell depleted mice showed a significant increase in the percentage of T-bet expressing CD4+ T cells in aortic plaques compared to control mice (αCD20: 25.05±2.88% vs. ctrl: 15.94±2.14%, p&lt;0.05). Furthermore, the percentage of RORyt+ and IL-17+ CD4+ T cells in the spleen and heart draining lymph nodes was increased after B cell depletion, indicating a shift towards Th17 differentiation.

Conclusions
Collectively, we show that CD20+ B cell depletion in aged LDLr-/- mice skews CD4+ T cells towards a Th1 phenotype in the atherosclerotic plaque and towards a Th17 phenotype in lymphoid organs, suggesting a protective role for aged B cells in atherosclerosis. However, B cells are a heterogeneous population and further research should elucidate whether aged B cells exert a pro- or anti-atherogenic role. In conclusion, our results indicate that aged B cells have an important function in CD4+ T cell differentiation and could be attractive targets to combat age-related cardiovascular disease.
Induction of CD73 prevents death after emergency open aortic surgery
Authors: Spicer AJS , Venermo MV , Hakovirta HH , Jalkanen JMJ 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Other. Main funding source(s): Faron Pharmaceuticals Ltd

Background
Cluster of differentiation (CD73) has been a focus of drug development in immuno-oncology for numerous years now. This however disregards the major role of CD73 in inflammatory conditions by the conversion of the majorly conserved and pro-inflammatory, adenosine triphosphate (ATP) to the equally conserved and anti-inflammatory, adenosine. Therefore the induction of CD73 for conditions of major inflammation would occur such as during times of ischemia post major surgery would be therapeutically beneficial. The therapeutic induction of CD73 has previously been shown in other inflammatory condtions by utilising intravenous interferon beta.
A ruptured abdominal aortic aneurysm (RAAA) is a medical emergency. Whilst rarely scene now due to improvements to screening, the only lifesaving treatment remains to be is immediate aortic surgery. Half of RAAA patients die before reaching the hospital and despite successful surgery another 30-40% of these patients die post-surgery in intensive care due to multi-organ failure (MOF).
The cause of MOF is systemic inflammatory response is brought forth by inflammatory mediators such as ATP, that are released from stressed and dying cells which perpetuate the cycle of inflammation.

Purpose
Can intravenous interferon beta-1a induce CD73 production and improve survival after emergency open surgery for a ruptured abdominal aortic aneurysm?

Methods
A multi-center phase II double-blind, randomised, parallel group comparison of the efficacy and safety of intravenous interferon beta-1a vs. placebo for the induction of CD73 to prevent death after open surgery for an infra-renal ruptured abdominal aortic aneurysm

Results
The initial aim of the trial, better RAAA survival after emergency surgery with INF beta-1a treatment could not be demonstrated due to the under powering of the trial. Nevertheless, the anticipated target mechanism, up-regulation of CD73 was associated with 100% survival. In tandem, both neutralising antibodies and systemic glucocorticoid blocked the up-regulation of CD73.

Conclusion
Contrary to the initial hypothesis IV IFN beta-1a did not prevent post operative RAAA mortality. Further studies are required to draw definitive conclusions as the clinical trial had to be stopped and did not reach the expected number of participants. Future trials should take into account the potential interaction with glucocorticoids and interferon beta-1a neutralising antibodies. Nonetheless, the anticipated target mechanism of up-regulation of CD73 was associated with survival and is a highly potential molecule to target to improve post-operative RAAA Survival
Observational medical treatment or surgery for giant paraesophageal hiatal hernia in elderly patients
Authors: Braghetto Italo , Molina Juan Carlos , Korn Owen , Lanzarini Enrique , Musleh Maher , Figueroa Manuel , Rojas Jorge 
Published: June 2022

Abstract
Giant paraesophageal hernias (GPHH) occur frequently in the elderly and account for about 5–10% of all hiatal hernias. Up to now controversy persists between expected medical treatment and surgical treatment. To assess if an indication for surgical repair of GPHH is possible in elderly patients. A prospective study that includes patients over 70 years of age hospitalized from January 2015 to December 2019 with GPHH. Patients were separated into Group A and Group B. Group A consisted of a cohort of 23 patients in whom observation and medical treatment were performed. Group B consisted of 44 patients submitted to elective laparoscopic hiatal hernia repair. Symptomatic patients were observed in both groups (20/23 in Group A and 38/44 in Group B). Charlson’s score &gt;6 and ASA II or III were more frequent in Group A. Patients in Group A presented symptoms many years before their hospitalization in comparison to Group B (21.8+7.8 vs. 6.2+3.5 years, respectively) (P=0.0001). Emergency hospitalization was observed exclusively in Group A. Acute complications were frequently observed and hospital stays were significantly longer in Group A, 14 patients were subjected to medical management and 6 to emergency surgery. In-hospital mortality occurred in 13/20 patients (65%) versus 1/38 patients (2.6%) in Group B (P=0.0001). Laparoscopic paraesophageal hiatal hernia repair can be done safely, effectively, and in a timely manner in elderly patients at specialized surgical teams. Advanced age alone should not be a limiting factor for the repair of paraesophageal hernias.
Changes in resonance frequency of rock columns due to thermoelastic effects on a daily scale: observations, modelling and insights to improve monitoring systems
Authors: Guillemot Antoine , Baillet Laurent , Larose Eric , Bottelin Pierre 
Published: June 2022

Summary
Slope instabilities, including prone-to-fall rock columns, are known to exhibit clear vibrational modes. The resonance frequencies of these modes can be tracked by seismic instrumentation, allowing the rock column's mechanical and structural properties to be monitored, as well as providing precursors of imminent irreversible failures. In previous studies, superficial thermoelastic effects were assumed to drive daily fluctuations in resonance frequencies, but no qualitative or quantitative evidence was provided. The results presented here corroborate this hypothesis and quantify the physical processes involved. We interpreted daily variations of resonance frequencies in the Les Arches study site (Vercors, French Prealps) using a thermo-mechanical finite-element model. Modelled fluctuations of the resonance frequencies over a day closely matched experimental observations, reproducing the daytime frequency increase of around 2 per cent. In addition, our model provides explanation of the various behaviours observed across study sites: the frequency response strongly depends on solar exposure, as well as the timing and intensity of both radiative and convective heat fluxes. We highlight acousto-elastic constants as key parameters of our semi-quantitative model, although they remain poorly constrained here. For future instrumentation, we therefore recommend the deployment of pyranometers on rocky sites to accurately invert these parameters over time, thus allowing rock fracturing to be quantitatively tracked by acousto-elastic monitoring.