bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)
Authors: Ferguson B.S , Stern J.A , Oldach M.S , Ueda Y , Ontiveros E.S , Napierski N.C , Del Rio C.L , Harris S.P 
Published: November 2020

Abstract

Introduction
Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling.

Methods
A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV).

Results
A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P&lt;0.05) and hyperdynamic contraction (FS: 61±4 vs. 50±3%, P&lt;0.05) relative to controls and presented with dynamic LVOT obstruction in 54% of cases. HCM cats had elevated end-diastolic pressures (17±1.4 vs. 9±1.0 mmHg, P&lt;0.05), with prolonged time constants of relaxation (60±4.1 vs. 36±2.4 ms, P&lt;0.05) and elevated end-diastolic stiffness (Eed: 0.44±0.06 vs. 0.25±0.01 mmHg/mL). Acute treatment with MYK-581 alleviated LVOT obstruction (0% vs. 38%), normalized contractility (FS: −7±2%), and increased systolic/diastolic chamber dimensions (e.g., LVIDd: +13±4%) (all P&lt;0.05), while reducing EDP (15±2 to 13±2 mmHg, P&lt;0.05), suggesting acute improvement in ventricular distensibility. Indeed, MYK-581 treatment reduced end-diastolic stiffness (Eed: 0.48±0.11 vs. 0.36±0. 10 mmHg/mL, P&lt;0.05) and normalized trans-mitral motion patterns during filling.

Conclusions
Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM.

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): MyoKardia
Reciprocal modulation of Linc-223 and its ligand miR-125a on the basis of platelet function level
Authors: De Rosa S , La Bella S , Canino G , Siller-Matula J , Eyleten C , Postula M , Tamme L , Iaconetti C , Sabatino J , Polimeni A , Sorrentino S , Gareri C , Proto L , Strangio A , Indolfi C 
Published: November 2020

Abstract

Background
Cardiovacular diseases (CVD) are the leading cause of death worldwide. Platelet play a key role in the pathophysiology of multiple CVD. LincRNAs are long non-coding RNAs transcribed from intergenic DNA segments. Some members of this class were recently associated with human disease. Linc-223 is co-transcribed together with mir-223 and was recently shown to bind to miR-125. Both miR-223 and miR-125 are highly expressed in platelets.

Purpose
In light of the capability of Linc-223 to bind to miR-125, we aimed to investigate whether their reciprocal expression levels might reflect the degree of platelet activity.

Methods
RNA was extracted using miRVANA. MiRNAs and lncRNAs were measured by means of quantitative Real Time RT-PCR.

Results
We found a significant reduction of Linc-223 levels (p&lt;0.05) along with a significant increase in miR-125 levels (p&lt;0.05) after initiation of any antiplatelet treatment (n=30) compared to naïve patients (n=10). Moreover, the upgrade to a higher-intensity antiplatelet treatment with ASA+ticagrelor from ASA+clopidogrel (n=30) was associated to a further down-regulation of Linc-223 (p&lt;0.05) along with a further increase of miR-125. (p&lt;0.05). Finally, these results were validated in a larger cohort of 300 patients from the ATLANTIS study, demonstrating significant modulation of both miR-223 and miR-125 in patients with high on-treatment platelet aggregation levels compared to antiplatelet-responsive patients.

Conclusions
We identify a reciprocal modulation of Linc-223 and miR-125, its ligand upon different levels of platelet aggregations. These results are compatible with previous evidence from patients with Acute Myeloid Leukemia, that Linc-223 might bind to and sponge miR-125, inhibiting its effect. These results suggest that plasma levels of Linc-223, miR-125 and miR-223 might be used a biomarkers of platelet finction in a clinical context, for risk stratification of patients or to assess the responsiveness to antiplatelet treatments.

Funding Acknowledgement
Type of funding source: None
The predictive role of endothelial glycocalyx in primary prevention of cardiovascular events:a 6 year follow-up study
Authors: Ikonomidis I , Thymis J , Katsanos S , Kousathana F , Varoudi M , Triantafyllou C , Kostelli G , Triantafyllidi H , Lambadiari V , Papadavid E , Plotas P , Tsilivarakis D , Benas D , Katogiannis K , Iliodromitis E.K 
Published: November 2020

Abstract

Introduction
Endothelial glycocalyx is a layer of glycoproteins on endothelial cells preventing vascular wall permeability to circulating proteins and blood cells. Perfused Boundary Region (PBR) of arterial microvessel is a non-invasive marker of endothelial glycocalyx thickness, as increased PBR indicates a reduced endothelial glycocalyx thickness. Cardiovasular risk factors and cardiovascular diseases have been associated with impaired PBR. However, PBR has not been studied as a predictor of major adverse cardiovascular events (MACE) in primary prevention.

Methods
We studied 400 adults, without history cardiovascular disease. We measured PBR of sublingual vessels with diameter 5–25μm by GlycoCheck Software using a dedicated camera (Sidefield Darkview Imaging, Microscan MV, Nederlands). We recorded a full medical history for each subject. The participants were followed up for a period of 6 years for major cardiovascular events (including Acute Coronary Syndrome, Stroke, decompensated acute heart failure, cardiovascular death and death of all causes).

Results
The mean age of participants was 49±10 years, 52% were males, 65% active smokers, 33.3% had hyperlipidemia, 12.8% type 2 Diabetes respectively, 30% hypertension and 20.5% had positive family history of premature coronary artery disease. The median PBR value was equal to 1.15 μm. After 6 years of follow up, 42 MACE were recorded (7 cardiovascular deaths). In univariate analysis, subjects with PBR values &gt;1.15μm had greater risk of adverse events compared with those that had lower PBR (relative risk RR=2.83, p&lt;0.05). Diabetes and hypertension were also univariate predictors of MACE (RR=3.71 and RR=2.51, p&lt;0.05). In multivariate analysis after adjusting for atherosclerotic risk factors including diabetes and hypertension, PBR remained a an independent predictor of MACE (RR=2.67, p&lt;0.05)

Conclusion
Endothelial glycocalyx thickness appears to be an important independent predictor of adverse cardiovascular outcomes.
Predictive value endothelial glycocalyx

Funding Acknowledgement
Type of funding source: None
CD40 levels in plasma are associated with cardiovascular disease and in carotid plaques with a vulnerable plaque phenotype and remodelling
Authors: Shami A , Edsfeldt A , Shore A.C , Natali A , Khan F , Nilsson J , Lutgens E , Goncalves I 
Published: November 2020

Abstract

Background and purpose
CD40 and CD40 ligand (CD40L) are costimulatory molecules and members of the TNF receptor superfamily well known for their involvement in inflammatory and autoimmune diseases. This study uses two large human cohorts – the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) and the Carotid Plaque Imaging Project (CPIP) – to explore the potential of plasma or intra-plaque expression of CD40 and CD40L as biomarkers and to locally affect plaque stability.

Methods
Proximity Extension Assay (PEA) technique was used to measure soluble CD40 and CD40L (sCD40 and sCD40L) in plasma from 1437 subjects from the SUMMIT cohort, the majority of which (80%) with pre-existing cardiovascular disease, and in atherosclerotic plaque homogenates from 199 subjects of the CPIP cohort undergoing carotid endarterectomy. The Mann-Whitney U test was used to compare groups and Spearman's rank correlation/the Chi-square test was used to assess correlations. Multiple comparisons were corrected for using the Holm-Šídák test. A logistic regression model was used to test for associations with future cardiovascular events and mortality.

Results
In the SUMMIT cohort both plasma CD40 and CD40L levels were elevated in individuals with a history of stroke (p=0.000030 and p=0.020, respectively), while sCD40 levels also were higher in individuals with a prior acute myocardial infarction (p=0.016). Plasma levels of sCD40 correlated with carotid plaque burden (as measured by ultrasound imaging, r=0.355, p&lt;1x10–16) and were associated with future cardiovascular events over a three year-follow up period (p=0.02, hazard ratio 1.3, 95% C.I: 1.042–1.625).
sCD40 and sCD40L were associated with a plaque phenotype characterized by the strong presence of features both of vulnerability such as high content oxidized low-density lipoprotein (LDL; r=0.236, p=0.004 and r=0.259, p=0.0037, respectively) and pro-inflammatory cytokines (e.g. tumour necrosis factor-α: p=3.1x10–7 and p=0.0006, respectively) and low calcium content (r=−0.208, p=0.012 and r=0.268, p=0.00034, respectively).

Conclusion
High plasma CD40 and CD40L levels are associated with symptomatic cardiovascular disease. Plasma CD40 levels correlate with the severity of carotid atherosclerosis and are associated with an increased risk for future cardiovascular events. Additionally, intra-plaque levels are associated with a vulnerable plaque phenotype. Our findings thus support the value of sCD40 and sCD40L both as biomarkers and therapeutic targets for cardiovascular disease.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): The Swedish Heart and Lung Foundation (1) and the Swedish Research Council (2)
Pemafibrate protects the rupture of experimental aortic aneurysm in mice through anti-oxidative stress with induced catalase
Authors: Amioka N , Miyoshi T , Akagi S , Yoshida M , Nakamura K , Morita H , Ito H 
Published: November 2020

Abstract

Background
Abdominal aortic aneurysm (AAA) is a life-threatening disease, while effective and preventive medical treatments remain unestablished.

Purpose
The aim of this study was to evaluate the effect of selective peroxi- some proliferator-activated receptor alpha (PPARα) modulator pemafibrate on AAA formation in mice.

Methods
AAA was induced by subcutaneous infusion of angiotensin II (AngII) in apolipoprotein E-deficient mice for 4 weeks. Treatment by pemafibrate or vehicle was started one week before AngII infusion. Oxidative stress was evaluated by dihydroethidium (DHE) staining.

Results
Prognosis after AngII infusion in pemafibrate-treated mice was significantly better than that in vehicle-treated mice (log-rang test, p=0.035) by reducing the occurrence of fatal AAA rupture. Meanwhile pemafibrate did not significantly reduce maximal diameter of the aorta. Histological findings demonstrated that the expression of collagen in adventitia in pemafibrate-treated mice was significantly greater than that in vehicle-treated mice (p&lt;0.05). Oxidative stress in aorta of pemafibrate-treated mice was significantly reduced comparing to vehicle-treated mice, accompanying by the reduction of mRNA expression of matrix metalloproteinase 2, tumor necrosis factor-α, and interleukin-6 (all p&lt;0.05). Catalase expression in abdominal aortic tissue was increased 1.5-fold in mice treated with pemafibrate than in mice treated with vehicle (p=0.032). In human vascular smooth muscle cells (hVSMC), pemafibrate attenuated AngII-induced oxidative stress (p&lt;0.001), which was canceled by administrating small interfering RNA (siRNA) of PPARα (p&lt;0.001). Furthermore, in hVSMC, pemafibrate increased catalase expression significantly (p&lt;0.001), while this increase was significantly suppressed by knockdown of PPAR-α with siRNA. (p&lt;0.001).

Conclusion
Pemafibrate reduced the rupture of AAA in this murine model, which is associated with anti-oxidative stress via catalase induction.

Funding Acknowledgement
Type of funding source: None
Comparative analysis of various metrics of arterial compliance in the study of chronic inflammatory diseases
Authors: Kerkhof P.L , Djorai R.B , Maslyanskiy A , Kolesova E , Konradi A.O , Shlyakhto E.V , Li J.K.-J 
Published: November 2020

Abstract

Introduction
Arterial compliance (AC), known to depend on age and sex, may be severely compromised in chronic inflammatory diseases. Apart from the various definitions for arterial stiffness that are in vogue, their constituent components are often not unique.

Purpose
This study compares vascular stiffness measures in various inflammatory diseases and explores a more comprehensive description of vessel wall properties by also considering inherent associated companion metrics.

Methods
We retrospectively analyzed arterial pressure, ventricular volume by echocardiography (Vivid-7 ultrasound system), along with carotid–femoral pulse wave velocity (PWV, by SphygmoCor, Atcor). Pulse pressure (PP) equals systolic arterial pressure (SAP) minus diastolic arterial pressure (DAP). Effective arterial elastance (Ea) = 0.9 × SAP/SV where SV is stroke volume. AC=SV/PP (Figure 1A). The intrinsic companion (C) to any established difference-based metric is calculated on the basis of the squared mean, e.g., PPC2 = (SAP2 + DAP2). Clearly, AC depends on two differences, each having a companion.

Results
A total of 177 patients (age range 18 to 80 years, 49 males), characterized by inflammatory disease (51 scleroderma, 62 atherosclerosis, 35 ankylosing spondylitis, and 29 rheumatoid arthritis), yielded reduced levels of vacular compliance irrespective of the method selected. Regression analysis showed weak correlations between the various approaches (i.e., Ea, AC, PWV). Average values for AC are comparable for all 4 diagnostic groups. Ea (P&lt;0.03) and PWV (P&lt;0.014) are lower for ankylosing spondylitis compared to all other groups, likely due to younger age and the higher prevalence of men. Ea is highest in atherosclerosis (P&lt;0.026) versus all other groups. SV is significantly higher in atherosclerosis (P&lt;0.03) compared to scleroderma and rheumatoid arthritis. However, the companions may differ (Figure 1B): PPC is significantly (P=0.017) higher in atherosclerosis (156.3±16.1 mmHg) vs scleroderma (147.2±23.0 mmHg), while SVC in ankylosing spondylitis is higher (P&lt;0.013) than in all other groups.

Conclusions
Arterial stiffness measures show poor correlation, suggesting limitations to their utility when studying the diagnostic groups described here. Consideration of the companion associated with each difference-based metric is warranted in order to perform a comprehensive analysis of clinical data when evaluating the impact on risk factors and prognosis.
Figure 1. A: Compliance components. B: Companions

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): Russian Science Foundation
Cavin-1 regulates BMP/Smad signaling through the interaction of Caveolin-1 with BMPRII in pulmonary artery endothelial cells
Authors: Tomita S , Nakanishi N , Ogata T , Tsuji Y , Sakamoto A , Higuchi Y , Matoba S 
Published: November 2020

Abstract

Background
Pulmonary hypertension (PH) is a progressive disease associated with poor outcome. Caveolin-1 (Cav1) is a component of caveolae and classified as a related gene of pulmonary arterial hypertension (PAH). Gene mutations of bone morphogenetic protein type II receptor (BMPRII) is a most common cause of PAH. BMPRII is localized in caveolae and associates with Cav1. However, the role of the Caveolin-Cavin system on the BMP/Smad signaling and the PAH progression has not been well-known.

Purpose
The aim of our study is to investigate the relationship between Caveolin-Cavin system and BMP/Smad signaling pathway and explore the mechanism of downstream signal transduction of BMP signaling by the interaction between Caveolin and BMPRII.

Methods
Cav1 knockout mice were used to assess PH and caveolae in pulmonary artery endothelial cells were observed by electron microscope. Cav1 and Cavin-1, which is a component of caveolae and form a complex with Cav1, were knocked-down in human pulmonary artery endothelial cell (hPAEC) using siRNA and phosphorylation of Smad signal was evaluated. Apoptosis of these cells was explored by flow cytometry. We investigated the interaction between Cav1 and BMPRII, and evaluated whether Cavin-1 affects this interaction and signal transduction of BMP signaling.

Results
As previously described, deletion of Cav1 revealed disappearance of caveolae in pulmonary artery endothelial cells (PAECs), and Cav1 knockout mice exhibited PH with pulmonary vascular remodeling and right ventricular hypertrophy. We then examined roles of Cav1 in human PAECs (hPAECs). Cav1 knockdown in hPAECs reduced phosphorylation of Smad 1/5/9. In addition, Cav1 knockdown significantly increased hypoxia-induced apoptosis in hPAEC. Knockdown of Cavin-1 reversed phosphorylation of Smad 1/5/9 decreased by Cav1 knockdown in BMP9 stimulation. Cavin-1 reversed the expression of BMPRII decreased by overexpression of Cav1. Cav1 was associated with Cavin-1 at the plasma membrane in PAECs. Cav1 also associated with BMPRII at the membrane of hPAECs that was inhibited by Cavin-1, and Cavin-1 reduced the localization of BMPRII to the membrane of hPAECs. These results suggest that BMPRII interacts with Cav1 via Cavin-1-associated localization at the plasma membrane in hPAECs, resulting in regulating BMP/Smad signaling pathway and involving in the development of PAH.

Conclusions
Cavin-1 affects the interaction of Cav1 with BMPRII at the membrane of PAECs, and regulates BMP/Smad signaling. These results reveal a previously undescribed function of Cavin-Caveolin system in the development of PAH through regulation of BMP/Smad signaling.

Funding Acknowledgement
Type of funding source: None
Adipose extracellular signal-regulated kinase 2 protected from endothelial dysfunction and the oxidative stress of perivascular adipose tissue in obese mice
Authors: Osaki A , Sato Y , Endo S , Ito K , Kagami K , Yumita Y , Ishinoda Y , Toya T , Ido Y , Namba T , Adachi T 
Published: November 2020

Abstract

Introduction
Extracellular signal-regulated kinase (ERK) modulates differentiation and maturation of adipocyte and the hypertrophy and differentiation of adipocytes affected the vascular diseases in obese. Changes in characters of adipocytes could develope the oxidative stress and inflammations. Moreover, changes in perivascular adipose tissue (PVAT) could modulate vascular tonus in obesity. However, the role of adipose ERK2 in endothelial function and characters of PVAT in obese in vivo had not been clarified, yet.

Purpose
This study aims to elucidate the role of the adipose ERK2 in endothelial-dependent relaxation (EDR) in mice model of obesity. The role of PVAT in EDR was also assessed.

Methods and results
We created adipose-specific ERK2 knock out mice (AE2KO) by crossing fatty acid binding protein 4 Cre and ERK2 flox mice and fed them with normal diet (ND) or high fat/ high sucrose diet (HFHSD) for 24 weeks. AE2KO fed with HFHSD gained more weight and revealed the heterogeneity in sizes of adipocyte in subcutaneous fat (SF). Furthermore, the mRNA levels of lipoprotein lipase, hormone-sensitive lipase, and peroxisome proliferator-activated receptor γ, which was the master genes of adipocyte differentiation, were markedly down-regulated in SF. PVAT in AE2KO with HFHSD was markedly enlarged and the mRNA expression of inflammatory adipocytokines, such as IL-1β and leptin were up-regulated. Next, we assessed EDR by acetylcholine (ACh) -induced relaxation in aortic rings with or without PVAT. EDR without PVAT was modestly decreased in AE2KO with HFHSD compared with wild type mice (WT) with HFHSD. Aortic rings with PVAT increased EDR in WT with ND. PVAT modestly decreased EDR in WT with HFHSD and mostly eliminated EDR in AE2KO with HFHSD. To assess the contraction factors released from PVAT, the solutions incubated with PVAT (SIP) were transferred to the normal aortic rings. SIP from WT with HFHSD mildly increased vascular tone and SIP from AE2KO with HFHSD further increased it. Tempol, which was superoxide scavenger, restored endothelial dysfunction with PVAT and suppressed the contraction with SIP from AE2KO with HFHSD. Fluorescence intensity of dihydroethidium stain of aorta and PVAT, which indicated that aortic and adipose superoxide production were elevated in AE2KO with HFHSD, which were mostly eliminated with tempol.

Conclusions
Adipose ERK2 selectively modulated differentiation in SF, suppressed the aortic oxidative stress and protected from endothelial dysfunction in obese. Moreover, adipose ERK2 suppressed the hypertrophy, inflammation, and oxidative stress of PVAT in obese. The oxidative stress with the inflammation in PVAT released vasoconstriction factors, which contributed to endothelial dysfunction in obese mice.
Figure 1

Funding Acknowledgement
Type of funding source: None