Vessel Beds Research Articles

Intravascular Lithotripsy for Peripheral Artery Calcification: 30-Day Outcomes From the Disrupt PAD III Observational Study.

Intravascular lithotripsy (IVL) has shown promising safety and effectiveness in calcified peripheral artery disease (PAD) in large trials and small real-world experiences. Real-world evidence from a larger cohort is lacking, so we aimed to evaluate the real-world acute performance of IVL in the treatment of calcified PAD. The Disrupt PAD III Observational Study (OS) is a prospective, multicenter, single-arm study. Patients with claudication or critical limb-threatening ischemia (CLTI) and at least moderate calcification were eligible. Independent predictors of procedural outcomes were assessed by multivariable analysis. Between November 2017 and June 2021 across 30 global sites, 1373 patients with 1677 lesions (1531, 91.3% core lab evaluable) were enrolled. Diameter stenosis and lesion length was 80.6±17.6% and 93.5±74.3 mm, respectively. Target vessels included femoropopliteal (61%), iliac (15.8%), common femoral (10.7%), and infrapopliteal arteries (12.8%). Lesion characteristics included 31.1% chronic total occlusions (CTOs) and 19.3% long lesions (≥15 cm). At final assessment, residual stenosis was 23.8±11.3%, with 0.9% serious angiographic complications, no abrupt closures, distal embolization, no flow, or thrombotic events. Independent predictors of ≤30% residual stenosis were lesion length ≥15 cm (odds ratio [OR]=0.384), female sex (OR=1.850), age ≤75 years (OR=1.625), IVL balloon to artery ratio ≥1.0 (OR=1.538), and CTO lesions (OR=0.638). Lesion length ≥15 cm (OR=16.076) was an independent predictor of procedural complications. The Disrupt PAD III OS represents the largest assessment of IVL periprocedural outcomes in calcified PAD. It confirmed excellent procedural safety and effectiveness in complex lesions across multiple peripheral vascular beds. This final analysis of the PAD III OS represents the largest report of peripheral IVL utilization in daily clinical practice. The outcomes of this study indicate that previously reported procedural results in clinical trial settings can be translated to a broader patient population. Treatment with peripheral IVL in severely calcified stenotic lower limb lesions demonstrated consistent acute safety and stenosis reduction, even in complex patients across multiple vessel beds. In addition, the importance of proper IVL balloon sizing to achieve excellent acute stenosis reduction was confirmed by multivariate analysis.

Moderate hypothermic circulatory arrest with antegrade cerebral perfusion for the open repair of juxtarenal abdominal aortic aneurysm repair with shaggy aorta

Shaggy aorta is severe luminal surface degeneration of the aorta leading to an increased risk of plaque destabilization and embolization to the peripheral or visceral vessel beds. It represents a challenging clinical entity for both endovascular and open repair owing to potential atheroembolization, increased early morbidity and mortality, and poor long-term survival. Patients may be denied repair owing to its high risks. Herein, we present a novel approach to open repair of a juxtarenal abdominal aortic aneurysm with shaggy aorta using moderate hypothermic circulatory arrest with antegrade cerebral perfusion and concurrent flow modification to mitigate the risk of atheroma embolism.

Tumour vasculature at single-cell resolution.

Tumours can obtain nutrients and oxygen required to progress and metastasize through the blood supply1. Inducing angiogenesis involves the sprouting of established vessel beds and their maturation into an organized network2,3. Here we generate a comprehensive atlas of tumour vasculature at single-cell resolution, encompassing approximately 200,000 cells from 372 donors representing 31 cancer types. Trajectory inference suggested that tumour angiogenesis was initiated from venous endothelial cells and extended towards arterial endothelial cells. As neovascularization elongates (through angiogenic stages SI, SII and SIII), APLN+ tip cells at the SI stage (APLN+ TipSI) advanced to TipSIII cells with increased Notch signalling. Meanwhile, stalk cells, following tip cells, transitioned from high chemokine expression to elevated TEK (also known as Tie2) expression. Moreover, APLN+ TipSI cells not only wereassociated with disease progression and poor prognosis but also hold promise for predicting response to anti-VEGF therapy. Lymphatic endothelial cells demonstrated two distinct differentiation lineages: one responsible for lymphangiogenesis and the other involved in antigen presentation. In pericytes, endoplasmic reticulum stress was associated with the proangiogenic BASP1+ matrix-producing pericytes. Furthermore, intercellular communication analysis showed that neovascular endothelial cells could shape an immunosuppressive microenvironment conducive to angiogenesis. This study depicts the complexity of tumour vasculature and has potential clinical significance for anti-angiogenic therapy.

Shear stress and pathophysiological PI3K involvement in vascular malformations.

Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα (PIK3CA). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA-related vascular anomalies, or "PIKopathies," range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA-related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.

BRACHIAL, FEMORAL, AND SKIN HAEMODYNAMIC RESPONSES TO WALKING IN HOT CONDITIONS: COMPARISON BETWEEN MALES AND FEMALES

INTRODUCTION & AIMS Heat exposure induces acute changes in arterial function, but sex differences have not been fully addressed. METHODS Participants walked (5km/h; 2% incline) in a climate chamber (42°C;50%RH) for 120mins. Cutaneous microvascular function (laser doppler flowmetry), conduit artery haemodynamics (Doppler ultrasound) and core temperature were measured at baseline, and every 30min. RESULTS 14♂ and 15♀ completed 120min. At baseline, differences in core temperature (Tc) between males and females were not significant (37.2±0.1 vs 37.0±0.1°C; P=0.06). Across all 5 timepoints, females exhibited larger Tc than males (P=0.019). At baseline, males had larger brachial (3.89±0.11 vs 3.13±0.09mm, P<0.001) and femoral (6.22±0.16 vs 5.29±0.14mm, P=0.001) diameters than females. A significant interaction (P=0.047) indicated that brachial diameter increased more in response to heat exertion than in males, whereas no sex difference was apparent in femoral diameter change. Males and females had similar baseline brachial flows (♂80.1±11.2 vs ♀57.0±7.09ml/min, P=0.087), but males had larger baseline femoral flows (♂263.0±23.9 vs ♀151.5±18.6 ml/min, P=0.010). No sex differences were apparent in the terms of the increases in brachial or femoral flows. Finally, at baseline males and females had similar skin blood flux (♂22.6±2.7 vs ♀18.3±2.9PU), but males demonstrated larger increases during heat exertion (P=0.029). CONCLUSIONS Males exhibit larger baseline artery diameters and flows in vessel beds feeding active (femoral) and inactive (brachial) limbs. In response to heat exertion, men and women exhibit similar increases in conduit diameter and flow to active muscle beds (femoral responses). In the inactive forearms, which reflect thermoregulatory responses, females had larger brachial artery diameter changes, but blood flow responses were similar between the sexes and men demonstrated larger increases in skin perfusion. These data indicate that responses to heat exertion differ in the upper and lower limbs, with sex-differences apparent in each of these territories, and at distinct levels of the arterial hierarchy.

Histology of the internal reproductive organs of the female Arabian oryx (Oryx leucoryx).

The Arabian oryx (Oryx leucoryx) is an antelope that is considered a "vulnerable" species. Lack of knowledge on the structure of its reproductive organs hinders the development of strategies to improve its reproduction. There is only one report on the gross anatomy of the female reproductive organs. With the aim of describing their microanatomy, the ovaries, uterine tubes, uterus, and vagina were collected at necropsy of an adult female oryx. Samples from each organ were analyzed with H&E staining and light microscopy. The squamous to cuboidal germinal epithelium covers the dense tunica albuginea of the ovaries, which encloses the cortex. This merges smoothly with the medulla. The cortex embeds follicles at several stages of development. A rich bed of blood vessels is present in the medulla, especially at the hilum. The uterine tubes are comprised of a serosa, muscularis, and mucosa. The muscularis is constituted of circular smooth muscle covered by a thin layer of longitudinal fibers. The mucosa has longitudinal folds lined by a pseudostratified epithelium with ciliated cells. The uterine horns are constituted of a serosa, muscularis, and mucosa. The muscularis contains an inner circular layer of smooth muscle and an outer longitudinal one. Simple coiled glands are present at the base of the mucosa. From this, highly cellular projections (caruncles) are present, lined by a by a simple columnar epithelium. The cervix contains four dense rings, and its mucosa is lined by longitudinal folds of a simple columnar epithelium, with ciliated cells. Numerous glands are located in the lamina propria and contain simple cuboidal to columnar epithelium. The vaginal wall was made of a serosa, muscularis, and mucosa. The mucosa is made of stratified squamous epithelium non-keratinized. In summary, the histology of the internal reproductive organs of the oryx is like the one of other ruminants.

Preoperative Direct Puncture Embolization Using aNonadhesive Ethylene Vinyl Alcohol (EVOH) Liquid Embolic Agent for Head and Neck Paragangliomas.

This retrospective study aimed to assess the safety and technical efficacy of preoperative direct puncture embolization using anonadhesive ethylene vinyl alcohol (EVOH) copolymer-based liquid embolic agent (LEA) combined with balloon occlusion at the origin of the external carotid artery for head and neck paragangliomas (HNP). We conducted areview of all consecutive cases of HNPs treated with direct puncture embolization using EVOH-based LEAs between 2017 and 2022 in 2 tertiary high-volume hospitals. Atotal of 25cases of HNPs in 24patients underwent direct puncture embolization (12males, 12females, mean age 50.9 ± 15.6 years). The average lesion volume was 299.95 mm3. The mean procedure time was 139.11 min, and the mean volume of EVOHs used per case was 19.38 mL. Successful complete devascularization was achieved in all cases, with ahomogeneous and deep penetration of the embolic agent into the tumor vessel bed regardless of the LEA type. Preoperative embolization of HNPs using adirect puncture technique and EVOHs is asafe, efficient, and feasible treatment option with alow risk of complications. This procedure facilitates surgery by transforming tumors into avascular masses that are well-delineated against the surrounding normal tissue.

Long-Term Exposure to Fine Particulate Constituents and Vascular Damage in a Population with Metabolic Abnormality in China.

To date, PM2.5-associated vascular damage in metabolic abnormalities has remained controversial. We knew little about the vascular damage of PM2.5 constituents. Thus, this study aimed to investigate the relationship between long-term exposure to PM2.5 and its constituents and vascular damage in metabolic abnormalities. A total of 124,387 participants with metabolic abnormalities (defined as at least one metabolic disorder, such as obesity, elevated blood pressure, elevated triglyceride level, elevated fasting glucose level, or low HDL cholesterol level) were recruited in this study from 11 representative centers in China between January 2011 and December 2017. PM2.5 and its constituents (black carbon [BC], organic matter [OM], sulfate [SO42-], nitrate [NO3-], and ammonium salts [NH4＋]) were extracted. Elevated brachial-ankle pulse wave velocity (baPWV) (≥ 1,400 cm/s) and declined ankle-brachial index (ABI) (＜0.9) indicated vascular damage. Multivariable logistic regression and Quantile g-Computation models were utilized to explore the impact on outcomes. Of the 124,387 participants (median age, 49 years), 87,870 (70.64%) were men. One-year lag exposure to PM2.5 and its constituents was significantly associated with vascular damage in single pollutant models. The adjusted odds ratios (OR) for each 1-µg/m3 increase in PM2.5 was 1.013 (95% CI, 1.012-1.015) and 1.031 (95% CI, 1.025-1.037) for elevated baPWV and decreased ABI, respectively. PM2.5 constituents were also associated with vascular damage in multi-pollutant models. Among the PM2.5 constituents, BC (47.17%), SO42- (33.59%), and NH4＋ (19.23%) have the highest contribution to elevated baPWV and NO3- (47.89%) and BC (23.50%) to declined ABI. Chronic exposure to PM2.5 and PM2.5 constituents was related to vascular damage in the abnormal metabolic population in China. The heterogeneous contribution of different PM2.5 constituents to vessel bed damage is worthy of attention when developing targeted strategies.

Data dynamics of angiogenesis visualization instrumental methods in patients with psoriasis during methotrexate therapy: Clinical and prognostic value of dermatoscopy and ultrasound dopplerography

BACKGROUND: Pathological angiogenesis is one of the important pathogenetic links of psoriasis. At the same time, the prognostic significance of instrumental methods for studying the severity of angiogenesis in psoriatic plaques remains poorly understood.
 AIM: Clinical assessment of the correlation between the dynamics of angiogenesis parameters (morphometric parameters of vascular glomeruli and Doppler blood flow in the skin and nail bed) and indicators of the methotrexate clinical efficacy during 12 months of therapy.
 MATERIALS AND METHODS: The work is based on the clinical data analysis of 82 patients with moderate and severe psoriasis vulgaris in the acute stage, who were prescribed methotrexate after initial examination. Patients underwent Doppler ultrasound examination of the skin in psoriatic plaques area and digital dermatoscopy to study the characteristics of vascular angiogenesis loci before treatment and at 1, 3 and 12 months of methotrexate therapy.
 RESULTS: As a result of comparative correlation analysis of dermatoscopy and ultrasonographic Dopplerography indicators dynamics and psoriasis clinical index values during the treatment of patients with methotrexate, moderate and strong correlations were established between the values of the average diameter of the vascular glomerulus and the degree of increased blood flow in psoriatic plaque area after 1 month of methotrexate treatment and the values of PASI at 3, 6 and 12 months from the start of treatment (r=0.540.76, p=0.0020.005), as well as between the mean vascular glomerulus diameter values and the degree of skin blood flow increase after 3 months and PASI and BSI indices after 6 and 12 months (r=0.360.74, p=0.0010.036). Disappearance of Doppler signals in psoriatic plaques skin and decrease in vascular glomeruli average diameter after 1 month from the start of therapy in 1.76 [1.38; 2.30] and 1.30 [1.38; 2.30] times increase the probability of achieving clinical improvement after three months of methotrexate treatment. The correlation coefficient between the degree of NAPSI reduction after 6 and 12 months of treatment and the dynamics of Doppler blood flow in the nail bed and resistance index of arterial vessels in the nail bed after three months from the start of treatment varied from 0.53 to 0.73.
 CONCLUSIONS: The dynamics of instrumental methods indicators for studying pathological angiogenesis correlates with the probability of achieving clinical improvement in psoriasis symptoms during systemic methotrexate therapy.

Quantitative CTA vascular calcification, atherosclerosis burden, and stroke mechanism in patients with ischemic stroke

BackgroundVascular calcification is recognized as the advanced stage of atherosclerosis burden. We hypothesized that vascular calcium quantification in CT angiography (CTA) would be helpful to differentiate large artery atherosclerosis (LAA) from other stroke etiology in patients with ischemic stroke. MethodsWe studied 375 acute ischemic stroke patients (200 males, mean age 69.9 years) who underwent complete CTA images of the aortic arch, neck, and head. The automatic artery and calcification segmentation method measured calcification volumes in the intracranial internal carotid artery (ICA), cervical carotid artery, and aortic arch using deep-learning U-net model and region-grow algorithms. We investigated the correlations and patterns of vascular calcification in the different vessel beds among stroke etiology by age category (young: <65 years, intermediate: 65–74 years, older ≥75 years). ResultsNinety-five (25.3%) were diagnosed with LAA according to TOAST criteria. Median calcification volumes were higher by increasing the age category in each vessel bed. One-way ANOVA with Bonferroni correction showed calcification volumes in all vessel beds were significantly higher in LAA compared with other stroke subtypes in the younger subgroup. Calcification volumes were independently associated with LAA in intracranial ICA (OR; 2.89, 95% CI 1.56–5.34, P = .001), cervical carotid artery (OR; 3.40, 95% CI 1.94–5.94, P < .001) and aorta (OR; 1.69, 95%CI 1.01–2.80, P = .044) in younger subsets. By contrast, the intermediate and older subsets did not show a significant relationship between calcification volumes and stroke subtypes. ConclusionAtherosclerosis calcium volumes in major vessels were significantly higher in LAA compared to non-LAA stroke in younger age.

5613480 REAL WORLD APPLICATIONS OF CLINICAL WHOLE BLOOD ADHESION (VCAM AND P-SELECTIN) BIOMARKERS IN A PEDIATRIC SCD POPULATION

Background: Vaso-occlusive (VOC) pain is the most common complication in sickle cell disease (SCD) and is associated with increased morbidity and early mortality. VOC results from intravascular sickling, and decreased red blood cell deformability with increased inflammation and adhesion in the vessel bed. Recent data has demonstrated the ability of whole blood adhesion to vascular cell adhesion molecule (VCAM) and P-selectin (Psel) to stratify individuals with SCD according to their risk of developing a self-reported VOC. Literature regarding the clinical utility of whole blood adhesion biomarkers in pediatric patients with SCD is limited. Aims: We describe our real-world application of the flow adhesion of whole blood to VCAM-1(FA-WB-VCAM) and flow adhesion of whole blood to P-selectin(FA-WB-Psel) assays in pediatric patients with SCD. Methods: This was a cross-sectional analysis of baseline flow adhesion of whole blood to VCAM-1 and flow adhesion of whole blood to P-selectin indices obtained in children (<18 y/o) and young adult patients (18-21 y/o) with SCD at Children’s National Hospital in Washington, D.C. between January 2020 and March 2022. Both FA-WB-VCAM and FA-WB-Psel were performed by the Functional Fluidic laboratory in Detroit, MI. Changes in disease severity included increased VOC pain rate (home, emergency department, or hospital management), acute chest syndrome, priapism, and nephropathy. Statistical analysis included descriptive statistics, Pearson’s correlation, and categorical analysis by t-test(GraphPad, v9, 2021). P value <0.05 was statistically significant. Results: We identified 109 unique pediatric patients with FA-WB-VCAM and FA-WB-Psel assays performed as part of the standard of care. Eighty-seven percent were children (N=95), and 13% were young adults (N=14). The median age was 11 years(IQR 7-15 years), with 47% males (N=51) and 53% females (N=58). Sixty-two percent of patients were on hydroxyurea (N=68), 4.5% on crizanlizumab (N=5), 5.5% on voxelotor (N=6), and 3% on L-glutamine (N=3). FA-WB-VCAM was similar in children vs young adults [median (IQR): 242 (142-500) cells/m2 vs. 239 (134.8-324.8) cells/m2,p=0.0856] while FA-WB-Psel was higher in the young adult population [median (IQR):32 (11-52) cells/m2 vs. 45 (20-76.5) cells/m2, p=0.8681]. Seventy-four percent of patients were HgbSS, 22% Hgb SC, 2% HgbS Beta Thalassemia Zero, 1% Hgb SBeta Thalassemia Plus, and 1% Hgb SE. Baseline FA-WB-P-Sel and FA-WB-VCAM were performed as part of our standard of care. The most common indication for testing was for baseline evaluation (N=76, 70%), followed by a change in disease severity(N=18, 16%), pre-initiation of DMT/change in DMT (N=5, 4.5%), and a combination of change in disease severity and DMT (N=8, 7%). There were FA-WB-Psel values in patients with a change in disease severity vs. without (55.8 vs. 37.28 cells/m2, p=0.036), but no difference in FA-WB-VCAM (299.7 vs. 329.2 cells/m2, p=0.729). There was an inverse correlation between FA-WB-VCAM-1 and HgbF levels (Pearson’s R = 0.483, p<0.001). Conclusions: We established preliminary mean values of FA-WB-Psel and FA-WB-VCAM adhesion indices within all SCD genotypes. FA-WB-VCAM was higher in children while FA-WB-Psel was higher in young adults. Our data represents the expected differences in HgbSS and HgbSC phenotypes. FA-WB-Psel values were most reflective of a recent change in disease severity and may represent an attractive target to monitor SCD clinical severity.

Dynamically regulated focal adhesions coordinate endothelial cell remodelling in developing vasculature.

The assembly of a mature vascular network involves coordinated endothelial cell (EC) shape changes, including the process of EC elongation. How EC elongation is dynamically regulated in vivo is not fully understood. Here, we have generated a zebrafish mutant that is deficient for the integrin adaptor protein Talin 1 (Tln1). Using a new focal adhesion (FA) marker line expressing endothelial Vinculinb-eGFP, we demonstrate that EC FAs function dynamically and are lost in our tln1 mutants, allowing us to uncouple the primary roles of FAs in EC morphogenesis from the secondary effects that occur due to systemic vessel failure or loss of blood flow. Tln1 loss led to compromised F-actin rearrangements, perturbed EC elongation and disrupted cell-cell junction linearisation in vessel remodelling. Finally, chemical induction of actin polymerisation restored actin dynamics and EC elongation during vascular morphogenesis. Together, we identify that FAs are essential for EC elongation and junction linearisation in flow-pressured vessels and that they influence actin polymerisation in cellular morphogenesis. These observations can explain the severely compromised vessel beds and vascular leakage observed in mutant models that lack integrin signalling. This article has an associated 'The people behind the papers' interview.

The joint association of arteriosclerosis and plasma amyloid with cognitive function: the population‐based Rotterdam Study

AbstractBackgroundAlzheimer's disease and vascular brain injury are the most common causes of dementia, and are present jointly in 40% of individuals at time of death. Yet, the interaction between Alzheimer's and vascular pathology on cognition is largely undetermined. We studied the interaction between arteriosclerosis and plasma biomarkers of Alzheimer's disease on cognition in a general population without dementia.MethodOn stored plasma samples, obtained between 2002‐2005, we measured plasma levels of amyloid‐β40 and amyloid‐β42 by Simoa assay in 2252 participants of the population‐based Rotterdam Study (mean age: 68.9 years, 52% women). Arteriosclerosis was assessed using arterial calcification volumes that were quantified (semi‐)automatically on unenhanced computed tomography (CT). We captured the systemic burden of calcification, using a principal component analysis of calcification volumes in 4 different arterial vessel beds (intracranial and extracranial carotid arteries, coronary arteries and aortic arch). Cognitive assessment included the verbal fluency test, the letter‐digit substitution task, a 15‐word learning test, the Stroop test, and Purdue pegboard task. Global cognition (g‐factor) was calculated using a principal component analysis of these tests. We then determined the interaction between plasma amyloid‐β and calcification on cognitive performance, using multivariable linear regression models.ResultPlasma levels of amyloid‐β and systemic arteriosclerosis were both associated with poorer cognitive performance. After mutual adjustment in multivariable models only calcification remained significantly associated (beta [95%CI] for g‐factor per 1‐SD increase in amyloid‐β40: ‐0.02 [‐0.07; 0.03]; amyloid‐β42: 0.03 [‐0.01; 0.08]; and calcification burden: ‐0.06 [‐0.09; ‐0.04]). The association between amyloid‐β and cognition was stronger in individuals with higher burden of calcification (Figure 1), particularly for amyloid‐β40 (interaction amyloid‐β40×calcification: p = 0.04; amyloid‐β42×calcification: p = 0.001). Results were broadly similar across cognitive tests. The observed interaction between amyloid‐β40 and calcification volume was most profound for calcification burden in the intracranial carotid artery and aortic arch.ConclusionArteriosclerosis and amyloid‐β display synergistic effects on cognition in the general population. This interaction was more profound for amyloid‐β40 than for amyloid‐β42, suggesting our observations may relate particularly to amyloid angiopathy.

Real World Applications of Clinical Whole Blood Adhesion (VCAM and P-selectin) Biomarkers in a Pediatric SCD Population

Background: Vaso-occlusive (VOC) pain is the most common complication in sickle cell disease (SCD) and is associated with increased morbidity and early mortality. VOC is the result of intravascular sickling, decreased red blood cell deformability with increased inflammation and adhesion in the vessel bed. Recent data has demonstrated the ability of whole blood adhesion to both vascular cell adhesion molecule (VCAM) and P-selectin (Psel) to stratify individuals with SCD according to their risk of developing a self-reported VOC. Literature regarding the clinical utility of whole blood adhesion biomarkers in pediatric patients with SCD is limited. We describe our real-world application of the flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) and flow adhesion of whole blood to P-selectin (FA-WB-Psel) assays in pediatric patients with SCD. Methods: This was a cross sectional analysis of baseline flow adhesion of whole blood to VCAM-1 and flow adhesion of whole blood to P-selectin indices obtained in children (<18 y/o) and young adult patients (18-21 y/o) with SCD at Children's National Hospital in Washington, D.C. between January 2020 and March 2022. Both FA-WB-VCAM and FA-WB-Psel were performed by the Functional Fluidic laboratory in Detroit, MI following overnight shipping at 4-8oC. Change in disease severity included increased VOC pain rate (home, emergency department or hospital management), acute chest syndrome, priapism, and nephropathy. Change in disease modifying therapy (DMT) included new SCD-specific pharmacologic agent or dose increases for effect (not including minor adjustments for weight gain). Statistical analysis included descriptive statistics, Pearson's correlation, and categorical analysis by t-test (GraphPad, v9, 2021). P value <0.05 was statistically significant. Results: We identified 109 unique pediatric patients with FA-WB-VCAM and FA-WB-Psel assays performed as part of the standard of care. Eighty-seven percent were children (N=95), and 13% were young adults (N=14). The median age was 11 years (IQR 7-15 years), with 47% males (N=51) and 53% females (N=58). Sixty-two percent of patients were on hydroxyurea (N=68), 4.5% on crizanlizumab (N=5), 5.5% on voxelotor (N=6), and 3% on Endari (N=3). FA-WB-VCAM was similar in children vs young adults [median (IQR): 242 (142-500) cells/m2 vs. 239 (134.8-324.8) cells/m2, p=0.0856] while FA-WB-Psel was higher in the young adult population [median (IQR): 32 (11-52) cells/m2 vs. 45 (20-76.5) cells/m2, p=0.8681]. Seventy-four percent of patients were HgbSS, 22% Hgb SC, 2% Hgb SBeta Thalassemia Zero, 1% Hgb SBeta Thalassemia Plus, and 1% Hgb SE. Baseline FA-WB-P-Sel and FA-WB-VCAM was performed as part of our standard of care. The most common indication for testing was for baseline evaluation (N=76, 70%), followed by a change in disease severity (N=18, 16%), pre-initiation of DMT/change in DMT (N=5, 4.5%), and a combination of change in disease severity and DMT (N=8, 7%). There were two patients (2%) that had an acute clinical event, including splenic sequestration and crizanlizumab-infusion related VOC. There were FA-WB-Psel values in patients with a change in disease severity vs. without (55.8 vs. 37.28 cells/m2, p=0.036) but no difference in FA-WB-VCAM (299.7 vs. 329.2 cells/m2, p=0.729). Figure 1 represents a comparison of average FA-WB-VCAM (Fig 1A)(362.4±271 vs 216.8±138 cells/m2, p<0.001) and FA-WB-PSEL (Fig 1B)(46.4±49 vs 27.83±24 cells/m2, p=0.0138) values between HgbSS (N=81) and HgbSC (N=24) genotypes. There was an inverse correlation between FA-WB-VCAM-1 and HgbF levels (Pearson's R = 0.483, p<0.001). Conclusions: We established preliminary mean values of FA-WB-Psel and FA-WB-VCAM adhesion indices within all SCD genotypes. FA-WB-VCAM was higher in children while FA-WB-Psel was higher in young adults. Our data represents the expected differences in HgbSS and HgbSC phenotypes with patients with HgbSS reflecting higher adhesion values. There was also an inverse correlation to VCAM-1 and Hgb F levels, consistent with an improvement in RBC health in response to HgbF induction. FA-WB-Psel values were most reflective of a recent change in disease severity and may represent an attractive target to monitor and predict risk of changes in SCD severity. Future studies will measure serially pre vs. post therapeutic intervention and from VOC pain hospitalization to outpatient follow-up clinic visits in pediatric SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Volumetric imaging reveals VEGF-C-dependent formation of hepatic lymph vessels in mice.

The liver is a major biosynthetic and detoxifying organ in vertebrates, but also generates 25%–50% of the lymph passing through the thoracic duct and is thereby the organ with the highest contribution to lymph flow. In contrast to its metabolic function, the role of the liver for lymph generation and composition is presently severely understudied. We took a rigorous, volume imaging-based approach to describe the microarchitecture and spatial composition of the hepatic lymphatic vasculature with cellular resolution in whole mount immune stained specimen ranging from thick sections up to entire mouse liver lobes. Here, we describe that in healthy adult livers, lymphatic vessels were exclusively located within the portal tracts, where they formed a unique, highly ramified tree. Ragged, spiky initials enmeshed the portal veins along their entire length and communicated with long lymphatic vessels that followed the path of the portal vein in close association with bile ducts. Together these lymphatic vessels formed a uniquely shaped vascular bed with a delicate architecture highly adapted to the histological structure of the liver. Unexpectedly, with the exception of short collector stretches at the porta hepatis, which we identified as exit point of the liver lymph vessels, the entire hepatic lymph vessel system was comprised of capillary lymphatic endothelial cells only. Functional experiments confirmed the space of Disse as the origin of the hepatic lymph and flow via the space of Mall to the portal lymph capillaries. After entry into the lymphatic initials, the lymph drained retrograde to the portal blood flow towards the exit at the liver hilum. Perinatally, the liver undergoes complex changes transforming from the main hematopoietic to the largest metabolic organ. We investigated the time course of lymphatic vessel development and identified the hepatic lymphatics to emerge postnatally in a process that relies on input from the VEGF-C/VERGFR-3 growth factor—receptor pair for formation of the fully articulate hepatic lymph vessel bed.

Numerical Analysis on Effect of Coronary Supply-Demand Equilibrium on Varying Coronary Blockage and Stress Conditions.

In this paper, we present a computational fluid dynamic (CFD) analysis to capture the effect of physical stress and stenosis severity in coronary arteries leading to changes in coronary supply demand oxygen equilibrium. We propose a coupled Od-3d coronary vessel model to predict the variation in flow dynamics of coronary as well as arterial system, modeled using an in-silico model replicating cardiovascular hemodynamics. CFD simulation were solved using subject specific CT scan for coronary and arterial flow and pressure along with metrics related to arterial wall shear stress. Simulations were performed for three heart rates (75, 90 and 120 bpm) and four stenosis states representing different stages of Coronary artery disease (CAD) namely healthy, 50%, 75%, 90% blockage in left anterior descending artery (LAD). Myocardial oxygen supply demand equilibrium were calculated for each cases using hemodynamic surrogate markers naming Diastolic pressure time index for supply and Tension time index for demand. The proposed 0d-3d coupled hemodynamic model of the coronary vessel bed along with supply-demand equilibrium estimated for different stress level and stenosis severity may provide useful insights on the dynamics of CAD manifestation and predict vulnerable regions in coronary bed for early screening and interventions.

A simple agent-based model to simulate 3D tumor-induced angiogenesis considering the evolution of the hypoxic conditions of the cells

In tumors, angiogenesis (conformation of a new vasculature from another primal one) is produced with the releasing of tumor angiogenic factors from hypoxic cells. These angiogenic substances are distributed around the tumor micro-environment by diffusion. When they reach the primal blood vessel bed, the sprouting and branching of a new micro-vascular network is produced. These new capillaries will supply oxygen to cells so that their hypoxic state is overcome. In this work, a new and simple 3D agent-based model to simulate tumor-induced angiogenesis is presented. In this approach, the evolution of the hypoxic conditions in cells along the related conformation of the new micro-vessels is considered. The importance that the relative position of the primal vasculature and tumor structure takes in the final distribution of the new micro-vasculature has also been addressed. The diffusion of angiogenic factors and oxygen has been modelled at the targets by numerical convolution superposition of the analytical solution from the sources. Qualitative and quantitative results show the importance of tip endothelial cells in overcoming hypoxic conditions in cells at early stages of angiogenesis. At final stages, anastomosis plays an important role in the reduction of hypoxia in cells.

Prospective evaluation of impact of post‐Cesarean section uterine scarring in perinatal diagnosis of placenta accreta spectrum disorder

ABSTRACTObjectiveStandardized ultrasound imaging and pathology protocols have recently been developed for the perinatal diagnosis of placenta accreta spectrum (PAS) disorders. The aim of this study was to evaluate prospectively the effectiveness of these standardized protocols in the prenatal diagnosis and postnatal examination of women presenting with a low‐lying placenta or placenta previa and a history of multiple Cesarean deliveries (CDs).MethodsThis was a prospective cohort study of 84 consecutive women with a history of two or more prior CDs presenting with a singleton pregnancy and low‐lying placenta/placenta previa at 32–37 weeks' gestation, who were referred for perinatal care and management between 15 January 2019 and 15 December 2020. All women were investigated using the standardized description of ultrasound signs of PAS proposed by the European Working Group on abnormally invasive placenta. In all cases, the ultrasound features were compared with intraoperative and histopathological findings. Areas of abnormal placental attachment were identified during the immediate postoperative gross examination and sampled for histological examination. The data of a subgroup of 32 women diagnosed antenatally as non‐PAS who had complete placental separation at birth were compared with those of 39 cases diagnosed antenatally as having PAS disorder that was confirmed by histopathology at delivery.ResultsOf the 84 women included in the study, 42 (50.0%) were diagnosed prenatally as PAS and the remaining 42 (50.0%) as non‐PAS on ultrasound examination. Intraoperatively, 66 (78.6%) women presented with a large or extended area of dehiscence and 52 (61.9%) with a dense tangled bed of vessels or multiple vessels running laterally and craniocaudally in the uterine serosa. A loss of clear zone was recorded on grayscale ultrasound imaging in all 84 cases, while there was no case with bladder‐wall interruption or with a focal exophytic mass. Myometrial thinning (< 1 mm) in at least one area of the anterior uterine wall was found in 41 (97.6%) of the 42 cases diagnosed as non‐PAS on ultrasound and 37 (88.1%) of the 42 diagnosed antenatally as PAS. Histological samples were available for all 48 hysterectomy specimens with abnormal placental attachment and for the three cases managed conservatively with focal myometrial resection and uterine reconstruction. Villous tissue was found directly attached to the superficial myometrium (placenta creta) in six of these cases and both creta villous tissue and deeply implanted villous tissue within the uterine wall (placenta increta) were found in the remaining 45 cases. There was no evidence of percreta placentation on histology in any of the PAS cases. Comparison of the main antenatal ultrasound signs and perioperative macroscopic findings between the two subgroups correctly diagnosed antenatally (32 non‐PAS and 39 PAS) showed no significant difference with respect to the distribution of myometrial thinning and the presence of a placental bulge on ultrasound and of anterior uterine wall dehiscence intraoperatively. Compared with the non‐PAS subgroup, the PAS subgroup showed significantly higher placental lacunae grade (P < 0.001) and more often hypervascularity of the uterovesical/subplacental area (P < 0.001), presence of bridging vessels (P = 0.027) and presence of lacunae feeder vessels (P < 0.001) on ultrasound examination, and increased vascularization of the anterior uterine wall intraoperatively (P < 0.001).ConclusionsRemodeling of the lower uterine segment following CD scarring leads to structural abnormalities of the uterine contour on both ultrasound examination and intraoperatively, independently of the presence of accreta villous tissue on microscopic examination. These anatomical changes are often reported as diagnostic of placenta percreta, including cases with no histological evidence of PAS. Guided histological examination could improve the overall diagnosis of PAS and is essential to obtain evidence‐based epidemiologic data. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Revisiting the gut-liver axis: gut lymphatic system in liver cirrhosis and portal hypertension.

The lymphatic vascular system runs parallel to the blood vascular system, comprising a network of lymphatic vessels and secondary lymphoid organs. The intestinal lymphatic capillaries (lacteals) and the associated collecting vessels in the mesentery form the gut lymphatic system. The gut lymphatic vasculature comprises the longest-studied lymphatic vessel bed and plays a significant role in the uptake and transport of dietary fat, abdominal fluid balance, and gut immunosurveillance. Gut is closely connected to liver through the portal circulation. In several experimental and clinical studies, the "gut-liver-axis" has been demonstrated to contribute to the pathogenesis of portal hypertension, liver cirrhosis, and its complications. Given a significant impact of gut health on the liver, in the current review, we highlight "gut-liver axis" in context to the circulatory physiology of gut lymphatic vessels. Despite their paramount importance in maintaining fluid and immune homeostasis in the gut, gut lymphatic vessels remain one of the most understudied physiological systems in liver disease pathology. In the current review, we delineate the connections of gut lymphatics with abdominal fluid homeostasis and bacterial translocation in the pathogenesis of liver cirrhosis and portal hypertension. We describe mechanisms and factors that drive gut lymphangiogenesis and lymphatic vessel dysfunction during inflammation. The review also underscores the role of gut lymphatic endothelial cells in regulating gut and liver immunity. We finally discuss the prognostic and therapeutic prospects of studying gut lymphatic vessels in advanced liver cirrhosis.

Features of angioarchitectonics and structure of the aortic wall of white rats in the early stages of experimental diabetes mellitus

Background. Atherosclerotic cardiovascular diseases, as well as coronary heart disease, cerebrovascular disease, and peripheral artery disease (probably caused by atherosclerosis), are the leading cause of disability and mortality in people with diabetes. Objective. The purpose of our study was to determine the histostructural features and morphometric analysis of the components of the aortic wall and its hemomicrocirculatory bed after 2 and 4 weeks of streptozotocin-induced diabetes mellitus. Methods. The samples for the histology were the sections of the wall of the ascending part, the aortic arch, and the descending part of the aorta of 26 mature white male rats weighing 100 - 160 g. For morphometric examination, a series of images of the aortic wall was taken using a Meiji MT4300 LED microscope with an x40 objective, x10 eyepiece. Results and conclusion. The measurements were carried out using the ImageJ software. The development of micro- and macroangiopathies in experimental animals with 8-week streptozotocin-induced diabetes mellitus was histologically proved. Statistical analysis revealed a significant difference of all morphometric parameters of both - the components of the aortic wall and the vessels of its hemomicrocirculatory bed after 4 weeks of experimental diabetes in comparison with the norm, control, and the 2-nd week of the experiment. An explicit dependency of the severity of destructive changes in the wall of the aorta and links of its hemomicrocirculatory bed of vessels on the duration of the experiment was determined.