Macular perfusion normative data acquired with optical coherence tomography angiography in healthy four-year-old Caucasian children

Background The purpose of this cross-sectional study involving healthy emmetropic four-year-old Caucasian children was to provide a macular perfusion normative database acquired with optical coherence tomography angiography (OCTA). One eye of each examinee underwent OCTA imaging. The following parameters were analyzed using AngioTool Image J software: vessels area (VA), vessels density (VD), total number of junctions (TNJ), junctions density (JD), total vessel length (TVL), average vessel length (AVL), total number of endpoints (TNEP), lacunarity (L), vessel diameter index (VDI), tortuosity (T) and foveal avascular zone (FAZ). Average central macular thickness (CMT) and average central macular volume (CMV) were measured. Result Sixty-two eyes of 62 children of average age 50.4 ± 3.8 months were examined. VA, VD, and T increased from the inner towards the outer layers of the retina. The intermediate capillary plexus had the highest JD and TNEP and narrowest FAZ. Retinal sexual differentiation was supported with higher values of the retinal VA, VDI and TNEP, and chorioretinal VA, VDI and L in males. The choriocapillaris presented with the highest VD, AVL, and T and the lowest L and TNEP. Conclusion The study provides the first detailed normative database of the macular vascular network in the youngest uniform cohort of emmetropic four-year-old children.

Neuroprotection in early stages of Alzheimer’s disease is promoted by transthyretin angiogenic properties

Background While still controversial, it has been demonstrated that vascular defects can precede the onset of other AD hallmarks features, making it an important therapeutic target. Given that the protein transthyretin (TTR) has been established as neuroprotective in AD, here we investigated the influence of TTR in the vasculature. Methods We evaluated the thickness of the basement membrane and the length of brain microvessels, by immunohistochemistry, in AβPPswe/PS1A246E (AD) transgenic mice and non-transgenic mice (NT) bearing one (TTR+/−) or two (TTR+/+) copies of the TTR gene. The angiogenic potential of TTR was evaluated in vitro using the tube formation assay, and in vivo using the chick chorioallantoic membrane (CAM) assay. Results AD transgenic mice with TTR genetic reduction, AD/TTR+/−, exhibited a thicker BM in brain microvessels and decreased vessel length than animals with normal TTR levels, AD/TTR+/+. Further in vivo investigation, using the CAM assay, revealed that TTR is a pro-angiogenic molecule, and the neovessels formed are functional. Also, TTR increased the expression of key angiogenic molecules such as proteins interleukins 6 and 8, angiopoietin 2, and vascular endothelial growth factor, by endothelial cells, in vitro, under tube formation conditions. We showed that while TTR reduction also leads to a thicker BM in NT mice, this effect is more pronounced in AD mice than in NT animals, strengthening the idea that TTR is a neuroprotective protein. We also studied the effect of TTR tetrameric stabilization on BM thickness, showing that AD mice treated with the TTR tetrameric stabilizer iododiflunisal (IDIF) displayed a significant reduction of BM thickness and increased vessel length, when compared to non-treated littermates. Conclusion Our in vivo results demonstrate the involvement of TTR in angiogenesis, particularly as a modulator of vascular alterations occurring in AD. Since TTR is decreased early in AD, its tetrameric stabilization can represent a therapeutic avenue for the early treatment of AD through the maintenance of the vascular structure.

Morphological and vascular characteristics of the optic nerve head in normal guinea pigs

The morphological and vascular characteristics of the optic nerve head (ONH) in normal guinea pigs remain unknown. Therefore, we aimed to investigate these parameters using optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). We measured the refractive error, axial length, and intraocular pressure (IOP), and performed OCT and OCTA of the ONH in 3- and 4-week-old tricolour guinea pigs. A total of 208 right eyes from 208 normal guinea pigs were examined. The refractive error in the 3-week group was significantly larger than that in the 4-week group (p < 0.001), the IOP in the 3-week group was significantly lower than that in the 4-week group (p = 0.014), and the circumpapillary retinal nerve fibre layer (cpRNFL) thickness in the 3-week group was significantly larger than that in 4-week group (p = 0.048). There were no significant differences in the average vessel area, vascular density, total number of junctions, total vessel length, total number of endpoints, and vascular diameter between the two groups. However, an age-adjusted linear regression analysis revealed that total vessel length was positively associated with the cpRNFL thickness (p = 0.024) and negatively associated with IOP (p = 0.016). This is the first report on morphological and vascular characteristics of the ONH in normal guinea pigs based on in vivo OCT and OCTA imaging and quantification of ONH parameters. These results may contribute to further research on myopia and glaucoma using guinea pig models.

Optical Coherence Tomography Angiography-Based Quantitative Assessment of Morphologic Changes in Active Myopic Choroidal Neovascularization During Anti-vascular Endothelial Growth Factor Therapy

Purpose: To establish quantitative profile of the morphologic changes among patients with active myopic choroidal neovascularization (mCNV) before and after anti-vascular endothelial growth factor (VEGF) therapy using optical coherence tomography angiography (OCTA) to assess the therapeutic response.Methods: Patients with active mCNV who received anti-VEGF injections between February 2017 to October 2020 and fit the study criteria were retrospectively reviewed. Quantitative analysis of their OCTA images were carried out to evaluate the morphologic features and vascular changes of mCNV lesions in response to anti-VEGF therapy. For further quantitative profiling, mCNV area, fractal dimension, vessel area, vessel density, vessel diameter, vessel length, vessel junction, junction density, and vessel tortuosity were obtained by means of advanced skeletonization postprocessing analyses.Results: Thirty-one eyes of 29 consecutive patients with OCTA-positive mCNV lesions (mean spherical equivalent: −12.55 ± 3.24 diopters) were included. The 31 cases were divided into two phenotypes at baseline: organized interlacing pattern (83.87%) and disorganized vascular loops pattern (16.13%). The values of mCNV area, fractal dimension, vessel area, vessel length, vessel junction, and junction density decreased remarkably 1 month after the initial anti-VEGF injection (p &lt; 0.001). Although, vessel density, vessel diameter, and vessel tortuosity increased meanwhile, only vessel diameter displayed statistical significance (p = 0.027). Of note, relative ratio analysis showed that vessel junction was the most sensitive biomarker in response to anti-VEGF therapy, reflecting a mean decrease of 50.36%. Sensitivity lowered successively in biomarkers of vessel length, vessel area, junction density, mCNV area, and fractal dimension. In addition, percent change of mCNV area (r = 0.552, p = 0.002), fractal dimension (r = 0.446, p = 0.017), vessel area (r = 0.518, p = 0.005), and vessel length (r = 0.440, p = 0.019) were moderately associated with that of central retinal thickness.Conclusions: The study showed morphological as well as quantitative changes on OCTA responding to anti-VEGF treatment in mCNV patients, among which vessel junctions might be the most predictive biomarker. OCTA-based analysis, providing intuitive images and a large spectrum of quantitative data at the same time, could promote new insights into the therapeutic response assessment in mCNV patients.

Neuroprotection in early stages of Alzheimers Disease is promoted by Transthyretin angiogenic properties

While still controversial, it has been demonstrated that vascular defects can precede the onset of the other AD hallmarks features, making it an important therapeutic target. Given that the protein transthyretin (TTR) has been established as neuroprotective in AD, here we investigated the influence of TTR in the vasculature. AD transgenic mice with TTR genetic reduction, AD/TTR+/-, exhibited a thicker BM in brain microvessels and decreased vessel length than animals with normal TTR levels, AD/TTR+/+. Further in vivo investigation, using the chick chorioallantoic membrane (CAM) assay, revealed that TTR is a pro-angiogenic molecule. Also, TTR increased the expression of key angiogenic molecules, by endothelial cells under tube formation conditions. We showed that TTR reduction leads to a thicker BM in AD mice than in NT animals, strengthening the idea that TTR is a neuroprotective protein. We also studied the effect of TTR tetrameric stabilization on BM thickness, showing that AD mice treated with iododiflunisal (IDIF) displayed a significant reduction of BM thickness and increased vessel length when compared to non-treated littermates. Our in vivo results show the involvement of TTR in angiogenesis, particularly as a modulator of vascular alterations occurring in AD. Since TTR is decreased early in AD, its tetrameric stabilization can represent a therapeutic avenue for the early treatment of AD through the maintenance of the vascular structure.

Optical Coherence Tomography Angiography Monitors Cutaneous Wound Healing under Angiogenesis-Promoting Treatment in Diabetic and Non-Diabetic Mice

During wound healing, the rapid re-establishment of a functional microcirculation in the wounded tissue is of utmost importance. We applied optical coherence tomography (OCT) angiography to evaluate vascular remodeling in an excisional wound model in the pinnae of C57BL/6 and db/db mice receiving different proangiogenic topical treatments. Analysis of the high-resolution OCT angiograms, including the four quantitative parameters vessel density, vessel length, number of bifurcations, and vessel tortuosity, revealed changes of the microvasculature and allowed identification of the overlapping wound healing phases hemostasis, inflammation, proliferation, and remodeling. Angiograms acquired in the inflammatory phase in the first days showed a dilation of vessels and recruitment of pre-existing capillaries. In the proliferative phase, angiogenesis with the sprouting of new capillaries into the wound tissue led to an increase of the OCT angiography parameters vessel density, normalized vessel length, number of bifurcations, and vessel tortuosity by 28–47%, 39–52%, 33–48%, and 3–8% versus baseline, respectively. After the peak observed on study days four to seven, the parameters slowly decreased but remained still elevated 18 days after wounding, indicating a continuing remodeling phase. Our study suggests that OCT angiography has the potential to serve as a valuable preclinical research tool in studies investigating impaired vascular remodeling during wound healing and potential new treatment strategies.

Minimal guidewire length for central venous catheterization of the right subclavian vein: A CT-based consecutive case series

Background: Central venous catheter (CVC) misplacement occurs frequently after right subclavian vein catheterization. It can be avoided by using ultrasound to confirm correct guidewire tip position in the lower superior vena cava prior to CVC insertion. However, retraction of the guidewire during the CVC insertion may dislocate the guidewire tip from its desired and confirmed position, thereby resulting in CVC misplacement. The aim of this study was to determine the minimal guidewire length required to maintain correct guidewire tip position in the lower superior vena cava throughout an ultrasound-guided CVC placement in the right subclavian vein. Methods: One hundred adult patients with a computed tomography scan of the chest were included. By using multiplanar reconstructions from thin-sliced images, the distance from the most plausible distal puncture site of the right subclavian vein to the optimal guidewire tip position in the lower superior vena cava was measured (vessel length). In addition, measurements of equipment in common commercial over-the-wire percutaneous 15–16 cm CVC kits were performed. The 95th percentile of the vessel length was used to calculate the required minimal guidewire length for each CVC kit. Results: The 95th percentile of the vessel length was 153 mm. When compared to the calculated minimal guidewire length, the guidewires were up to 108 mm too short in eight of eleven CVC kits. Conclusion: After confirmation of a correct guidewire position, retraction of the guidewire tip above the junction of the brachiocephalic veins should be avoided prior to CVC insertion in order to preclude dislocation of the catheter tip towards the right internal jugular vein or the left subclavian vein. This study shows that many commercial over-the-wire percutaneous 15–16 cm CVC kits contain guidewires that are too short for right subclavian vein catheterization, i.e., guidewire retraction is needed prior to CVC insertion.

Myocardial infarction triggers Inflammatory deterioration of vascular niche by accelerating loss of a specific vessel subtype in bone

Introduction The interface between heart and bone emerges as a key trigger of post-infarction inflammation and progression of chronic heart failure (CHF). However, our knowledge on the underlying mechanisms of this interaction is incomplete. Bone vasculature, specifically so-called H-type (Endomucinhigh) endothelial cells (EC), plays a crucial role in maintenance of the bone integrity and regulation of hematopoietic stem cells (HSC). While previous studies in mice showed the reduction of H-type vessels by aging, the impact of ischemic heart disease is unclear. Therefore, we aimed to investigate the effects of myocardial infarction (MI) and chronic heart failure on the vascular bone cell composition in mice and humans. Methods and results Flow cytometric analysis of harvested bones at the different timepoints after MI induction in mice revealed a gradual loss of H-type endothelial cells in the time-course of developing chronic heart failure (P&lt;0.05 at day 7 and 14 vs. control; P&lt;0.0001 at day 28 vs. control). This results were confirmed in immunostainings of tibia sections showing a significant decrease of H-type vessel length after MI (p&lt;0.05 at day 14 and 28, accordingly). The loss of type-H endothelium was accompanied by a significant expansion of long-term HSC in the bone (P=0.0005 at day 28 post MI vs. control). Importantly, type H ECs were also significantly reduced in the bone of ischemic post-infarct HF patients (n=16) compared with control subjects (n=8; P=0.0003). To gain insights into the mechanisms underlying the changes in the vascular niche, we performed single cells RNA sequencing of human BM ECs. These studies confirmed the decrease in Emcnexpressing ECs in ischemic HF patients, which was accompanied by significantly increased expression of inflammatory genes, including IL1b (P&lt;0.0001). Inflammatory EC phenotypes and IL1b expression in HF could be further confirmed at protein level using cytospin immunostainings. Murine studies further revealed an early induction IL-1b specifically in H-type vessels already at day 1 after MI induction, which preceded the loss of H-type endothelium within the following 4 weeks. By inhibiting IL-1b production using a specific Nlrp3 inflammasome inhibitor (MCC950) we could observe a partial restoration of H-type EC frequencies (P=0.033) and a significant increase in H-type vessel length (p=0.035) at day 28 day after MI. Conclusions Our data show for the first time an impact of myocardial infarction and chronic heart failure on the bone marrow vasculature. These changes seem to be strongly associated with inflammatory response in H-type vessels, which precedes its loss after MI. Specifically, the induction of the inflammatory cytokine IL1b may contribute to the disturbed phenotype. This suggest that inhibition of IL1b (e.g. by canakinumab) be used as a novel strategy to prevent or reverse the deterioration of the vascular bone function in ischemic heart disease. Funding Acknowledgement Type of funding source: None