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Temperature-responsive hydrogel-grafted vessel-on-a-chip: Exploring cold-induced endothelial injury.Biotechnology and Bioengineering Jul 2024Cold-induced vasoconstriction is a significant contributor that leads to chilblains and hypothermia in humans. However, current animal models have limitations in...
Cold-induced vasoconstriction is a significant contributor that leads to chilblains and hypothermia in humans. However, current animal models have limitations in replicating cold-induced acral injury due to their low sensitivity to cold. Moreover, existing in vitro vascular chips composed of endothelial cells and perfusion systems lack temperature responsiveness, failing to simulate the vasoconstriction observed under cold stress. This study presents a novel approach where a microfluidic bioreactor of vessel-on-a-chip was developed by grafting the inner microchannel surface of polydimethylsiloxane with a thermosensitive hydrogel skin composed of N-isopropyl acrylamide and gelatin methacrylamide. With a lower critical solution temperature set at 30°C, the gel layer exhibited swelling at low temperatures, reducing the flow rate inside the channel by 10% when the temperature dropped from 37°C to 4°C. This well mimicked the blood stasis observed in capillary vessels in vivo. The vessel-on-a-chip was further constructed by culturing endothelial cells on the surface of the thermosensitive hydrogel layer, and a perfused medium was introduced to the cells to provide a physiological shear stress. Notably, cold stimulation of the vessel-on-a-chip led to cell necrosis, mitochondrial membrane potential (ΔΨ) collapse, cytoskeleton disaggregation, and increased levels of reactive oxygen species. In contrast, the static culture of endothelial cells showed limited response to cold exposure. By faithfully replicating cold-induced endothelial injury, this groundbreaking thermosensitive vessel-on-a-chip technology offers promising advancements in the study of cold-induced cardiovascular diseases, including pathogenesis and therapeutic drug screening.
PubMed: 38946677
DOI: 10.1002/bit.28779 -
ESC Heart Failure Jul 2024Parameters derived from reservoir-excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir-excess pressure parameters...
AIMS
Parameters derived from reservoir-excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir-excess pressure parameters could have a detrimental effect on highly-perfused organs like the heart. We aimed to cross-sectionally determine whether reservoir-excess pressure parameters were associated with N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in older adults.
METHODS
We studied 868 older adults with diverse cardiovascular risk. Reservoir-excess pressure parameters were obtained through radial artery tonometry including reservoir pressure integral, peak reservoir pressure, excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC). Plasma levels of NT-proBNP, as a biomarker of cardiac overload, were analysed by the Proximity Extension Assay technology.
RESULTS
Multivariable linear regression analyses revealed that all reservoir-excess pressure parameters studied were associated with NT-proBNP after adjusting for age and sex. After further adjustments for conventional cardiovascular risk factors, INTXSP [β = 0.191 (95% confidence interval, CI: 0.099, 0.283), P < 0.001], SRC [β = -0.080 (95% CI: -0.141, -0.019), P = 0.010] and DRC [β = 0.138 (95% CI: 0.073, 0.202), P < 0.001] remained associated with NT-proBNP. Sensitivity analysis found that there were occasions where the association between SRC and NT-proBNP was attenuated, but both INTXSP and DRC remained consistently associated with NT-proBNP.
CONCLUSIONS
The observed associations between reservoir-excess pressure parameters and NT-proBNP suggest that altered reservoir-excess pressure parameters may reflect an increased load inflicted on the left ventricular cardiomyocytes and could have a potential to be utilized in the clinical setting for cardiovascular risk stratification.
PubMed: 38946623
DOI: 10.1002/ehf2.14926 -
Journal of Thrombosis and Haemostasis :... Jul 2024
Topics: Humans; Pulmonary Embolism; United States; Healthcare Disparities; Acute Disease; Reperfusion; Thrombolytic Therapy; Risk Factors; Treatment Outcome
PubMed: 38945666
DOI: 10.1016/j.jtha.2024.03.017 -
Journal of Nuclear Cardiology :... Jun 2024
PubMed: 38945427
DOI: 10.1016/j.nuclcard.2024.101904 -
The Journal of Heart and Lung... Jun 2024Many hearts offered for pediatric heart transplantation (HT) are not placed. In 2016, we initiated a quality improvement endeavor to increase heart offer acceptance....
BACKGROUND
Many hearts offered for pediatric heart transplantation (HT) are not placed. In 2016, we initiated a quality improvement endeavor to increase heart offer acceptance. This study assessed the effect of these interventions at our center.
METHODS
Evaluation of pre-/post-implementation cohorts (1/1/2008-12/31/2016 vs. 1/1/2017- 7/1/2023) comparing donor heart utilization. Six interventions were iterated over time to increase offer acceptance ("extended criteria"): ABO-incompatible transplant, ex vivo perfusion for distanced donors, 3-dimensional total cardiac volume (TCV) assessment, acceptance of Hepatitis-C or SARS-COV-2 infected donors, and institutional culture change favoring consideration of donors previously considered unacceptable (Public Health Service Risk, long CPR duration, etc.). Outcomes studied included annual HT volume, median waitlist duration, sequence number at acceptance, and post-transplant clinical outcomes.
RESULTS
From 1/2008-7/2023 annual transplant volume increased from 16/year to 25/year pre-/post-implementation. Three hundred-thirteen/389 (80%) listed patients were transplanted. Waitlist duration shortened post-implementation (P=0.01), as did the percentage of accepted heart offers utilizing at least one extended criterion (P<0.001). Institutional culture change and TCV assessment had the largest impact on donor heart utilization (P=0.04 &P<0.001). There was no difference in post-HT intubation or cardiovascular intensive care unit (CVICU) days (P= 0.05-0.9), though post-transplant hospitalization duration (P<0.001) increased. Post-transplant survival was unaffected by use of extended criteria hearts (P=0.3).
CONCLUSIONS
We report increased donor heart offer acceptance resulting from a longitudinal, multi-faceted effort to increase organ offer utilization, with institutional culture change and TCV assessments having the greatest impact. Use of extended criteria hearts was not associated with inferior survival.
PubMed: 38945282
DOI: 10.1016/j.healun.2024.06.015 -
Journal of Gastrointestinal and Liver... Jun 2024Ultra-microangiography (UMA) is a novel Doppler technique with optimized wall filtering that provides high sensitivity to low-velocity blood flows and optimized... (Comparative Study)
Comparative Study
BACKGROUND AND AIMS
Ultra-microangiography (UMA) is a novel Doppler technique with optimized wall filtering that provides high sensitivity to low-velocity blood flows and optimized visualization of microcirculation. The aim of this pilot study was to compare intestinal vascularization assessed by color Doppler signals (CDS) and UMA.
METHODS
We investigated intestinal vascularization using UMA and CDS in 13 patients with confirmed inflammatory bowel disease (IBD). A cohort of 28 patients without structural bowel disease served as the control.
RESULTS
Microcirculation and dysregulated microcirculation in patients without and with inflammatory bowel disease can be visualized and quantified using UMA. In 83 % of IBD patients and 76% of non-IBD patients, a high resolution of intestinal perfusion could be achieved using UMA.
CONCLUSIONS
To the best of our knowledge, this is the first study to investigate intestinal vascularization using UMA in patients with and without structural bowel disease. Quantification and visualization of intestinal vascularization should be further investigated in prospective studies and could help guide our therapy of patients with IBD.
Topics: Humans; Pilot Projects; Microcirculation; Female; Male; Adult; Middle Aged; Intestines; Inflammatory Bowel Diseases; Ultrasonography, Doppler, Color; Angiography; Aged; Young Adult; Predictive Value of Tests; Case-Control Studies
PubMed: 38944869
DOI: 10.15403/jgld-5495 -
Cell Reports Jun 2024Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with...
Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks. We adapted mouse organoids from normal pancreatic duct (mN10) and early pancreatic cancer (mP4, KRAS-G12D mutation, ± p53 knockout) from extracellular pH 7.4 to 6.7, representing acidic niches. Viability was increased by acid adaptation, a pattern most apparent in wild-type (WT) p53 organoids, and exacerbated upon return to pH 7.4. This led to increased survival of acid-adapted organoids treated with gemcitabine and/or erlotinib, and, in WT p53 organoids, acid-induced attenuation of drug effects. New genetic variants became dominant during adaptation, yet they were unlikely to be its main drivers. Transcriptional changes induced by acid and drug adaptation differed overall, but acid adaptation increased the expression of gemcitabine resistance genes. Thus, adaptation to acidosis increases cancer cell viability after chemotherapy.
PubMed: 38944837
DOI: 10.1016/j.celrep.2024.114409 -
Magnetic Resonance Imaging Clinics of... Aug 2024Monochorionic twins are at risk for complications due to the presence of placental vascular anastomoses, including twin-twin transfusion syndrome, twin... (Review)
Review
Monochorionic twins are at risk for complications due to the presence of placental vascular anastomoses, including twin-twin transfusion syndrome, twin anemia-polycythemia sequence, selective fetal growth restriction, and twin reversed arterial perfusion sequence. While ultrasound is the primary modality to screen for the development of these complications, MRI plays an important role in assessing monochorionic twin pregnancies for the development of other complications, such as neurologic injury. In this article, the authors review the ultrasound imaging findings associated with monochorionic twin complications, management options, and the role for MRI in these pregnancies.
Topics: Humans; Pregnancy; Fetoscopy; Female; Magnetic Resonance Imaging; Fetofetal Transfusion; Pregnancy, Twin; Ultrasonography, Prenatal; Twins, Monozygotic
PubMed: 38944438
DOI: 10.1016/j.mric.2024.02.010 -
Cancer Genomics & Proteomics 2024Patients with hypoxic bladder cancer benefit from hypoxia modification added to radiotherapy, but no biomarkers exist to identify patients with hypoxic tumours. We,...
BACKGROUND/AIM
Patients with hypoxic bladder cancer benefit from hypoxia modification added to radiotherapy, but no biomarkers exist to identify patients with hypoxic tumours. We, herein, aimed to implement oxygen-enhanced MRI (OE-MRI) in xenografts derived from muscle-invasive bladder cancer (MIBC) for future hypoxia biomarker discovery work; and generate gene expression data for future biomarker discovery.
MATERIALS AND METHODS
The flanks of female CD-1 nude mice inoculated with HT1376 MIBC cells. Mice with small (300 mm) or large (700 mm) tumours were imaged, breathing air then 100% O, 1 h post injection with pimonidazole in an Agilant 7T 16cm bore magnet interfaced to a Bruker Avance III console with a T2-TurboRARE sequence using a dynamic MPRAGE acquisition. Dynamic Spoiled Gradient Recalled Echo images were acquired for 5 min, with 0.1mmol/kg Gd-DOTA (Dotarem, Guerbet, UK) injected after 60 s (1 ml/min). Voxel size and field of view of dynamic contrast enhanced (DCE)-MRI and OE-MRI scans were matched. The voxels considered as perfused with significant post-contrast enhancement (p<0.05) in DCE-MRI scans and tissue were further split into pOxyE (normoxic) and pOxyR (hypoxic) regions. Tumours harvested in liquid N, sectioned, RNA was extracted and transcriptomes analysed using Clariom S microarrays.
RESULTS
Imaged hypoxic regions were greater in the larger versus smaller tumour. Expression of known hypoxia-inducible genes and a 24 gene bladder cancer hypoxia score were higher in pimonidazole-high versus -low regions: CA9 (p=0.012) and SLC2A1 (p=0.012) demonstrating expected transcriptomic behaviour.
CONCLUSION
OE-MRI was successfully implemented in MIBC-derived xenografts. Transcriptomic data derived from hypoxic and non-hypoxic xenograft regions will be useful for future studies.
Topics: Urinary Bladder Neoplasms; Animals; Humans; Mice; Magnetic Resonance Imaging; Female; Oxygen; Pilot Projects; Mice, Nude; Genomics; Hypoxia; Tumor Hypoxia; Cell Line, Tumor; Heterografts; Xenograft Model Antitumor Assays
PubMed: 38944425
DOI: 10.21873/cgp.20455 -
Journal of Oral Biosciences Jun 2024Xerostomia, a common complication of type 2 diabetes, leads to an increased risk of caries, dysphagia, and dysgeusia. Although anti-vascular endothelial growth factor...
OBJECTIVES
Xerostomia, a common complication of type 2 diabetes, leads to an increased risk of caries, dysphagia, and dysgeusia. Although anti-vascular endothelial growth factor (VEGF) antibodies, such as ranibizumab (RBZ), have been used to treat diabetic retinopathy, their effects on the salivary glands are unknown. This study evaluated the effects of RBZ on salivary glands to reduce inflammation and restore salivary function in a mouse model of type 2 diabetes.
METHODS
Male KK-A mice with type 2 diabetes (10-12 weeks old) were used. The diabetes mellitus (DM) group received phosphate-buffered saline, while the DM + RBZ group received an intraperitoneal administration of RBZ (100 μg/kg) 24 h before the experiment.
RESULTS
Ex vivo perfusion experiments showed a substantial increase in salivary secretion from the submandibular gland (SMG) in the DM + RBZ group. In addition, the mRNA expression levels of TNF-α and IL-1β were considerably lower in this group. In contrast, those of aquaporin 5 were substantially higher in the DM + RBZ group, as revealed by quantitative reverse transcription PCR. Furthermore, the number of lymphocyte infiltration spots in the SMG was notably lower in the DM + RBZ group. Finally, intracellular Ca signaling in acinar cells was considerably higher in the DM + RBZ group than that in the DM group.
CONCLUSION
Treating a type 2 diabetic mouse model with RBZ restored salivary secretion through its anti-inflammatory effects.
PubMed: 38944342
DOI: 10.1016/j.job.2024.06.011