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Journal of Biophotonics Sep 2023To investigate the alterations in the retinal vasculature and microstructure in dry-type high myopia.
BACKGROUND
To investigate the alterations in the retinal vasculature and microstructure in dry-type high myopia.
METHODS
One hundred and eighty-nine dry-type high myopia eyes were classified into three groups. Group 1 consisted of 86 eyes with no myopic retinal degenerative lesion (C0). Group 2 consisted of 71 eyes with tessellated fundus (C1). Group 3 consisted of 32 eyes with diffuse chorioretinal atrophy (C2). Retinal vascular density and retinal thickness were measured with optical coherence tomography angiography. The scanning area was a 3 × 3 mm ring with the fovea of the macular. All data were analyzed with the SPSS 23.0 by one-way ANOVA test among comparison groups. Pearson's correlation analysis was used to determine the relations among measurements. Univariate linear regression showed a correlation between the vascular densities and retinal thicknesses.
RESULTS
The microvessel density significantly decreased and significant thinning of the superior and temporal macular thickness in the C2 group. The vascular densities of macular decreased significantly with the increase of axial length (AL) and refractive diopter in the C2 group. The retinal thicknesses of the macular fovea increased significantly with the increase of vascular densities in the C0 group and C1 group.
CONCLUSIONS
The impairment of retinal microstructure is more likely related to reduced oxygen and nutrients due to microvessel density decreases.
Topics: Humans; Myopia; Retina; Retinal Vessels; Fundus Oculi; Microvessels
PubMed: 37099397
DOI: 10.1002/jbio.202200390 -
Molecular and Cellular Biochemistry Sep 2023Monoamine oxidases (MAOs), mitochondrial enzymes with two isoforms, A and B, have been recently recognized as significant contributors to oxidative stress in the...
Monoamine oxidases (MAOs), mitochondrial enzymes with two isoforms, A and B, have been recently recognized as significant contributors to oxidative stress in the cardiovascular system. The present study was purported to assess the effect of metformin and empagliflozin on MAO expression, oxidative stress and vascular reactivity in internal mammary arteries harvested from overweight patients with coronary heart disease subjected to bypass grafting. Vascular rings were prepared and acutely incubated (12 h) with high glucose (GLUC, 400 mg/dL) or angiotensin II (AII, 100 nM) and metformin (10 µM) and/or empagliflozin (10 µM) and used for the assessment of MAO expression (qRT-PCR and immune histochemistry), reactive oxygen species (ROS, confocal microscopy and spectrophotometry), and vasomotor function (myograph). Ex vivo stimulation with GLUC or AII increased both MAOs expression, ROS production and impaired relaxation to acetylcholine (ACh) of the vascular rings. All effects were alleviated by incubation with each antidiabetic drug; no cumulative effect was obtained when the drugs were applied together. In conclusion, MAO-A and B are upregulated in mammary arteries after acute stimulation with GLUC and AII. Endothelial dysfunction and oxidative stress were alleviated by either metformin or empagliflozin in both stimulated and non-stimulated vascular samples harvested from overweight cardiac patients.
Topics: Humans; Reactive Oxygen Species; Mammary Arteries; Metformin; Overweight; Vascular Ring; Oxidative Stress; Monoamine Oxidase
PubMed: 36583793
DOI: 10.1007/s11010-022-04633-8 -
JACC. Cardiovascular Interventions Sep 2023The MITRAL (Mitral Implantation of Transcatheter Valves) trial is the first prospective trial to evaluate the safety and feasibility of balloon-expandable aortic...
BACKGROUND
The MITRAL (Mitral Implantation of Transcatheter Valves) trial is the first prospective trial to evaluate the safety and feasibility of balloon-expandable aortic transcatheter heart valves in patients with failed surgical bioprostheses or annuloplasty rings and severe mitral annular calcification treated with mitral valve-in-valve (MViV), valve-in-ring (MViR), or valve-in-mitral annular calcification (ViMAC).
OBJECTIVES
The aim of this study was to evaluate 5-year outcomes among these patients.
METHODS
A multicenter prospective study was conducted among patients at high surgical risk at 13 U.S. sites. Patients underwent MViV (n = 30), MViR (n = 30), or ViMAC (n = 31) and were followed annually for 5 years. Kansas City Cardiomyopathy Questionnaire scores were obtained at baseline and follow-up visits. Echocardiograms were analyzed at independent core laboratories.
RESULTS
A total of 91 patients underwent transcatheter mitral valve replacement (February 2015 to December 2017). The mean age was 74.3 ± 8.9 years. At 5-year follow-up, the lowest all-cause mortality was observed in the MViV group (21.4%), 94.7% of patients were in NYHA functional class I or II, and the mean mitral gradient was 6.6 ± 2.5 mm Hg. The MViR and ViMAC groups had higher all-cause mortality (65.5% and 67.9%), most survivors were in NYHA functional classes I and II (50% and 55.6%), and mean mitral gradients remained stable (5.8 ± 0.1 and 6.7 ± 2.5 mm Hg). Significant improvements in Kansas City Cardiomyopathy Questionnaire scores were observed when all 3 arms were pooled.
CONCLUSIONS
MViV, MViR, and ViMAC procedures were associated with sustained improvement of heart failure symptoms and quality of life among survivors at 5 years. Transcatheter heart valve function remained stable in all 3 groups. Patients treated with MViV had excellent survival at 5 years, whereas survival was lower in the MViR and ViMAC groups, consistent with underlying disease severity. Patients with more residual mitral regurgitation had higher mortality.
Topics: Humans; Aged; Aged, 80 and over; Mitral Valve; Heart Valve Prosthesis Implantation; Prospective Studies; Quality of Life; Treatment Outcome; Cardiac Catheterization; Heart Valve Diseases; Heart Valve Prosthesis; Mitral Valve Insufficiency; Calcinosis; Vascular Diseases; Cardiomyopathies
PubMed: 37758379
DOI: 10.1016/j.jcin.2023.06.041 -
Astrocytoma and glioblastoma IDH1-wildtype cells colonize tumor vessels and deploy vascular mimicry.Ultrastructural Pathology Jul 2023Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular...
Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular aspects have been published; however, these were not complemented with ultrastructural evidence. Our ultrastructural examination of glioma vessels reveals several unique and critical features related to their mechanisms of progression and metastasis strategy. The detailed ultrastructural survey of 18 isocitrate dehydrogenase-wildtype (IDH1-wt) glioblastomas and 12 isocitrate dehydrogenase-mutant (IDH1-mt) High-grade gliomas indicated that tumor vessels of both types had undergone deformities such as the thickening of the vessel wall (VW) and proliferation of the basement membrane, contour distortions, abnormal and discontinuous basal lamina, tumor cells' invasion and colonization of VW, disappearance of endothelial cells (ECs), pericytes, and smooth muscle cells, as well as the formation of a continuous ring of tumor cells attached to the luminal side of VW in numerous cases. The latter feature is a clear sign of vascular mimicry (VM) that was previously suggested in gliomas but never shown by TEM. Additionally, the vascular invasion was carried out by a large number of tumor cells and was accompanied by the accumulation of tumor lipids in the vessels' lumina and VWs; these two features are distinct for gliomas and may alter the course of the clinical presentation and overall prognosis. This raises the issue of how to specifically target tumor cells involved in vascular invasion in order to optimize prognosis and overcome these mechanisms employed by the tumor cells.
Topics: Humans; Glioblastoma; Isocitrate Dehydrogenase; Endothelial Cells; Astrocytoma; Glioma; Brain Neoplasms; Mutation
PubMed: 37144386
DOI: 10.1080/01913123.2023.2205927 -
Association Between Airway Stenosis Degree and Respiratory Distress in Infants With a Vascular Ring.Cureus Oct 2023Background Although the number of cases of prenatally diagnosed vascular rings is increasing, some cases may remain asymptomatic, and no indicator of the appearance of...
Background Although the number of cases of prenatally diagnosed vascular rings is increasing, some cases may remain asymptomatic, and no indicator of the appearance of dyspnea has been established. Thus, we aimed to determine the relationship between the degree of airway compression by the vascular ring on contrast-enhanced computed tomography (CT) and respiratory distress. Methods This is a retrospective study of nine patients diagnosed with vascular rings at a single hospital from July 2010 to December 2019. Data regarding the patient's clinical characteristics, such as prenatal diagnosis, vascular ring type, complicated cardiac disease, and presence or absence of surgery, were recorded. Airway assessment on contrast-enhanced CT was measured in the axial cross-section. Statistical analysis was performed using Statistical Product and Service Solutions (SPSS) (version 25.0; IBM SPSS Statistics for Windows, Armonk, NY). Results Five of the eight patients had respiratory distress. Patients with respiratory distress were less likely to have been diagnosed prenatally (p = 0.04) and had smaller stenosis degree of anteroposterior diameter (p = 0.03). Conclusion Contrast-enhanced CT is useful in patients with vascular rings. Our study suggests that the stenosis degree of the anterior-posterior diameter of the airway is related to dyspnea.
PubMed: 37965390
DOI: 10.7759/cureus.47022 -
European Journal of Cardio-thoracic... Jul 2023Annuloplasty rings are routinely used in mitral valve repair (MVr). However, accurate annuloplasty ring size selection is essential to obtain a favourable outcome....
OBJECTIVES
Annuloplasty rings are routinely used in mitral valve repair (MVr). However, accurate annuloplasty ring size selection is essential to obtain a favourable outcome. Moreover, ring sizing can be challenging in some patients and is highly influenced by surgeons' experience. This study investigated the utility of three-dimensional mitral valve (3D-MV) reconstruction models to predict annuloplasty ring size for MVr.
METHODS
A total of 150 patients undergoing minimally invasive MVr with annuloplasty ring due to Carpentier type II pathology and who were discharged with none/trace residual mitral regurgitation were included. 3D-MV reconstruction models were created with a semi-automated software package (4D MV Analysis) to quantitate mitral valve geometry. To predict the ring size, univariable and multivariable linear regression analyses were performed.
RESULTS
Between 3D-MV reconstruction values and implanted ring sizes, the highest correlation coefficients were provided by commissural width (CW) (0.839; P < 0.001), intertrigonal distance (ITD) (0.796; P < 0.001), annulus area (0.782; P < 0.001), anterior mitral leaflet area (0.767; P < 0.001), anterior-posterior diameter (0.679; P < 0.001) and anterior mitral leaflet length (0.515; P < 0.001). In multivariable regression analysis, only CW and ITD were found to be independent predictors of annuloplasty ring size (R2 = 0.743; P < 0.001). The highest level of agreement was achieved with CW and ITD, and 76.6% of patients received a ring with no >1 ring size difference from the predicted ring sizes.
CONCLUSIONS
3D-MV reconstruction models can support surgeons in the decision-making process for annuloplasty ring sizing. The present study may be a first step towards accurate annuloplasty ring size prediction using multimodal machine learning decision support.
Topics: Humans; Mitral Valve; Mitral Valve Insufficiency; Cardiac Surgical Procedures; Tricuspid Valve; Mitral Valve Annuloplasty; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Treatment Outcome
PubMed: 37233202
DOI: 10.1093/ejcts/ezad212 -
Biochimica Et Biophysica Acta.... Apr 2024Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and...
AIMS
Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive.
MAIN METHODS
We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice.
KEY FINDINGS
Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway.
CONCLUSIONS
Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.
Topics: Animals; Chick Embryo; Humans; Mice; Rats; Endothelial Cells; Guanine Nucleotide Exchange Factors; Phosphatidylinositol 3-Kinases; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Neovascularization, Pathologic
PubMed: 38447883
DOI: 10.1016/j.bbadis.2024.167114 -
Biomolecules Dec 2023Vascular calcification (VC) is an age-related complication characterised by calcium-phosphate deposition in the arterial wall driven by the osteogenic transformation of...
Vascular calcification (VC) is an age-related complication characterised by calcium-phosphate deposition in the arterial wall driven by the osteogenic transformation of vascular smooth muscle cells (VSMCs). The JAK-STAT pathway is an emerging target in inflammation. Considering the relationship between VC and inflammation, we investigated the role of JAK-STAT signalling during VSMC calcification. Human aortic smooth muscle cells (HASMCs) were cultured in high-inorganic phosphate (Pi) medium for up to 7 days; calcium deposition was determined via Alizarin staining and colorimetric assay. Inflammatory factor secretion was evaluated via ELISA and JAK-STAT members' activation using Western blot or immunohistochemistry on HASMCs or calcified aortas of Vitamin D-treated C57BL6/J mice, respectively. The JAK-STAT pathway was blocked by JAK Inhibitor I and Von Kossa staining was used for calcium deposits in murine aortic rings. During Pi-induced calcification, HASMCs released IL-6, IL-8, and MCP-1 and activated JAK1-JAK3 proteins and STAT1. Phospho-STAT1 was detected in murine calcified aortas. Blocking of the JAK-STAT cascade reduced HASMC proliferation and pro-inflammatory factor expression and release while increasing calcium deposition and osteogenic transcription factor RUNX2 expression. Consistently, JAK-STAT pathway inhibition exacerbates mouse aortic ring calcification ex vivo. Intriguingly, our results suggest an alternative link between VSMC inflammation and VC.
Topics: Humans; Animals; Mice; Muscle, Smooth, Vascular; Calcium; Janus Kinases; STAT Transcription Factors; Signal Transduction; Vascular Calcification; Inflammation
PubMed: 38254629
DOI: 10.3390/biom14010029 -
Cellular and Molecular Life Sciences :... Aug 2023The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels...
The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels of key cellular proteins. While the CSN and its catalytic subunit CSN5 have been extensively studied in cancer, its role in inflammatory and neurological diseases is less understood. Following verification that CSN5 is expressed in mouse and human brain, here we studied the role of the CSN in neuroinflammation and ischemic neuronal damage employing models of relevant brain-resident cell types, an ex vivo organotypic brain slice culture model, and the CRL NEDDylation state-modifying drugs MLN4924 and CSN5i-3, which mimic and inhibit, respectively, CSN5 deNEDDylase activity. Untargeted mass spectrometry-based proteomics revealed that MLN4924 and CSN5i-3 substantially alter the microglial proteome, including inflammation-related proteins. Applying these drugs and mimicking microglial and endothelial inflammation as well as ischemic neuronal stress by TNF and oxygen-glucose-deprivation/reoxygenation (OGD/RO) treatment, respectively, we could link CSN5/CSN-mediated cullin deNEDDylation to reduction of microglial inflammation, attenuated cerebral endothelial inflammation, improved barrier integrity, as well as protection from ischemic stress-induced neuronal cell death. Specifically, MLN4924 reduced phagocytic activity, motility, and inflammatory cytokine expression of microglial cells, and this was linked to inhibition of inflammation-induced NF-κB and Akt signaling. Inversely, Csn5 knockdown and CSN5i-3 increased NF-κB signaling. Moreover, MLN4924 abrogated TNF-induced NF-κB signaling in cerebral microvascular endothelial cells (hCMECs) and rescued hCMEC monolayers from OGD/RO-triggered barrier leakage, while CSN5i-3 exacerbated permeability. In an ex vivo organotypic brain slice model of ischemia/reperfusion stress, MLN4924 protected from neuronal death, while CSN5i-3 impaired neuronal survival. Neuronal damage was attributable to microglial activation and inflammatory cytokines, as indicated by microglial shape tracking and TNF-blocking experiments. Our results indicate a protective role of the CSN in neuroinflammation via brain-resident cell types involved in ischemic brain disease and implicate CSN activity-mimicking deNEDDylating drugs as potential therapeutics.
Topics: Humans; Animals; Mice; Neuroinflammatory Diseases; COP9 Signalosome Complex; NF-kappa B; Cullin Proteins; Endothelial Cells; Brain; Inflammation; Cytokines
PubMed: 37597109
DOI: 10.1007/s00018-023-04911-8 -
JACC. Heart Failure May 2024In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction.
OBJECTIVES
This study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization.
METHODS
The treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro-B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported.
RESULTS
There were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro-B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo.
CONCLUSIONS
Additional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).
Topics: Humans; Heart Failure; Stroke Volume; Male; Female; Aged; Pyrimidines; Middle Aged; Hospitalization; Natriuretic Peptide, Brain; Peptide Fragments; Double-Blind Method; Treatment Outcome; Heterocyclic Compounds, 2-Ring
PubMed: 38363272
DOI: 10.1016/j.jchf.2023.12.005