Ultrasound-Induced Release of Nimodipine from Drug-Loaded Block Copolymer Micelles: In Vivo Analysis

Nimodipine prevents cerebral vasospasm and improves functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). The beneficial effect is limited by low oral bioavailability of nimodipine, which resulted in an increasing use of nanocarriers with sustained intrathecal drug release in order to overcome this limitation. However, this approach facilitates only a continuous and not an on-demand nimodipine release during the peak time of vasospasm development. In this study, we aimed to assess the concept of controlled drug release from nimodipine-loaded copolymers by ultrasound application in the chicken chorioallantoic membrane (CAM) model. Nimodipine-loaded copolymers were produced with the direct dissolution method. Vasospasm of the CAM vessels was induced by means of ultrasound (Physiomed, continuous wave, 3 MHz, 1.0 W/cm2). The ultrasound-mediated nimodipine release (Physiomed, continuous wave, 1 MHz, 1.7 W/cm2) and its effect on the CAM vessels were evaluated. Measurements of vessel diameter before and after ultrasound-induced nimodipine release were performed using ImageJ. The CAM model could be successfully carried out in all 25 eggs. After vasospasm induction and before drug release, the mean vessel diameter was at 57% (range 44–61%) compared to the baseline diameter (set at 100%). After ultrasound-induced drug release, the mean vessel diameter of spastic vessels increased again to 89% (range 83–91%) of their baseline diameter, which was significant (p = 0.0002). We were able to provide a proof of concept for in vivo vasospasm induction by ultrasound application in the CAM model and subsequent resolution by ultrasound-mediated nimodipine release from nanocarriers. This concept merits further evaluation in a rat SAH model. Graphical abstract

Unruptured Intradural Posterior Circulation Dissecting/Fusiform Aneurysms Natural History and Treatment Outcome

Background The natural history and outcome of unruptured posterior circulation dissecting fusiform aneurysms is not fully understood. These have a high risk of morbidity and mortality, not only due to natural history but also due to the challenging and controversial treatment approaches currently available compared to other types of intracranial aneurysms. Methods We performed a retrospective study of a prospectively collected aneurysm database at a quaternary neurovascular hospital. We included consecutive patients with unruptured intradural vertebrobasilar dissecting aneurysms between January 2000 and July 2016 who were followed to 2020. Description of baseline, procedural, and outcomes data was performed. Comparisons of patient who had aneurysm rupture on follow-up, increase in 2 or more points of mRS in follow-up and progression of the aneurysm was performed. Results Seventy patients with 78 fusiform posterior circulation aneurysms were identified. Thirty-nine (55.7%) patients were male with a mean age of 51.7 years (SD ± 17.6). When multiple, aneurysms were more likely to be fusiform (60%) than saccular (40.0%). Baseline diameter (measured on CTA/MRA/DSA), length as well as symptomatic presentation were significantly higher in aneurysms which grew over time. Coronary disease, diabetes and growth were associated an >2 increase in mRS. Diabetes as well as initial symptomatic presentation were associated with rupture. Conclusions Unruptured dissecting/fusiform aneurysm are associated with a considerable rate of rupture during follow-up. Growth is associated with morbidity even in the absence of rupture. Initial large size, coronary disease, diabetes, and to a lesser extent female gender may merit closer follow-up and/or prophylactic treatment.

Smaller size is more suitable for pharmacotherapy among undersized abdominal aortic aneurysm: a systematic review and meta-analysis

Background: Pharmacotherapy for undersized abdominal aortic aneurysm (AAA) is a clinical unmet need. Randomized controlled trials (RCTs) have failed to show effectiveness despite countless promising data in preclinical studies. We aimed to identify the population with undersized AAAs (30–54 mm) who potentially benefit from pharmacotherapy. Methods: In accordance with the PRISMA statement, we conducted a systematic review and meta-analysis of placebo-controlled RCTs. The primary outcome was mean difference (MD) in annual growth rate (< 0 favors pharmacotherapy), and the secondary outcome was aneurysm-related events (diameters ⩾ 55 mm, ruptures, or referral to surgery). Results: Our search strategy identified eight RCTs (six trials on antibiotics [ABx], two on renin-angiotensin system inhibitors [RAS-I]) with a total of 1325 patients. The mean of baseline diameters ranged from 33.1 mm to 43.1 mm. Neither ABx nor RAS-I showed significant differences in MD. Multivariable random-effects restricted maximum likelihood meta-regression revealed a statistically significant linear relationship between baseline diameter and MD (coefficient 0.15 [95% CI 0.0011, 0.30], p = 0.049) but not for the follow-up period ( p = 0.28) and duration of treatment ( p = 0.11). In line with this result, ABx with baseline diameter < 40 mm significantly reduced MD (−1.03 mm/year [95% CI −1.64, −0.42], p = 0.001) and a borderline significant difference in aneurysm-related events (HR 0.53 [95% CI 0.28, 1.00], p = 0.05), whereas the other groups ⩾ 40 mm never demonstrated effectiveness. Fixed-effect models did not change the results. No evidence of publication bias was detected. Conclusion: Undersized AAAs < 40 mm can potentially benefit from pharmacotherapy. Future RCTs should consider preferentially including undersized AAA with smaller diameters.

Outcomes of active surveillance of EU-TIRADS 5 thyroid nodules

Objective Active surveillance of cytologically proven microcarcinomas has been shown as a safe procedure. However, fine needle aspiration biopsy (FNAB) is not recommended by European Thyroid Association (ETA) and American Thyroid Association (ATA) guidelines for highly suspicious nodules ≤ 10 mm. The aim of the study was to assess the outcomes of active surveillance of EU-TIRADS 5 nodules ≤ 10 mm not initially submitted to FNAB. Patients and methods 80 patients with at least one EU-TIRADS 5 nodule ≤ 10 mm and no suspicious lymph nodes, accepting active surveillance, were included. Results Mean baseline diameter and volume were 5.4 mm (±2.0) and 64.4 mm3 (±33.5), respectively. After a median follow-up of 36.1 months, a volumetric increase ≥ 50% occurred in 28 patients (35.0%) and a suspicious lymph node in 3 patients (3.8%). Twenty-four patients underwent an FNAB (30.0%) after at least a 1 year follow-up of which 45.8% were malignant, 8.3% benign, 33.3% undetermined and 8.3% nondiagnostic. Sixteen patients (20.0%) underwent conversion surgery after a median follow-up of 57.2 months, confirming the diagnosis of papillary carcinoma in 15/16 cases (not described in 1 histology report), all in remission at 6–12 months postoperative follow-up. Conclusion Applying ETA and ATA guidelines to avoid FNA of EU-TIRADS 5 sub-centimeter nodules and proceeding to active surveillance of such nodules in selected patients is a safe procedure. Thus, US-FNAB could be postponed until the nodule shows signs of progression or a suspicious lymph node appears, with no added risk for the patient.

Restoration of Afferent Arteriolar Autoregulatory Behavior in Ischemia-Reperfusion Injury in Rat Kidneys

Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR) induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60-minutes of bilateral renal artery occlusion followed by 24 hours of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65±3% of baseline diameter (13.2±0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7±0.5 µm and remained between 90-101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (Tempol or apocynin) to IR kidneys for 20 minutes increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, addition of polyethylene glycol superoxide dismutase (PEG-SOD) or polyethylene glycol catalase (PEG-catalase) to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and MCP-1 in renal tissue homogenates and this was prevented by Tempol pre-treatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion.

Sex and light physical activity impact popliteal, but not brachial artery flow-mediated dilation in physically active young adults

When controlling for baseline diameter, males have greater brachial flow-mediated dilation (BA-FMD) responses than females. It is unclear whether sex differences in baseline diameter also influences popliteal FMD (POP-FMD), which may be impacted by cardiorespiratory fitness and physical activity levels. We hypothesized that males would exhibit greater BA-FMD and POP-FMD when allometrically scaled to baseline diameter. FMD (ultrasonography), cardiorespiratory fitness (indirect calorimetry), and objectively measured physical activity were assessed in males (n = 13; age, 23 ± 3 years; peak oxygen consumption, 48.0 ± 7.1 mL·kg−1·min−1) and females (n = 13; age, 24 ± 2 years; peak oxygen consumption, 36.8 ± 6.0 mL·kg−1·min−1). Both groups had similarly high levels of moderate-to-vigorous intensity physical activity (503 ± 174 vs. 430 ± 142 min·week−1, p = 0.25). However, males were more aerobically fit (p < 0.001) and females accumulated more light-intensity physical activity (182 ± 67 vs. 127 ± 53 min·week−1, p = 0.03). Relative and allometrically scaled BA-FMD were similar (both, p ≥ 0.09) between sexes. In contrast, relative (6.2% ± 1.0% vs. 4.6% ± 1.4%, p = 0.001) and scaled (6.8% ± 1.7% vs. 4.7% ± 1.7%, p = 0.03) POP-FMD were greater in females. Relative POP-FMD was related to light-intensity physical activity in the pooled sample (r = 0.43; p = 0.04). However, the enhanced relative POP-FMD in females remained after adjusting for higher light-intensity physical activity levels (p = 0.01). Young females have enhanced popliteal, but not brachial, endothelial health than males with similar moderate-to-vigorous intensity physical activity levels and higher cardiorespiratory fitness. Novelty In physically active adults, females had greater POP-FMD but not BA-FMD than males. The enhanced POP-FMD in females was not related to greater vascular smooth muscle sensitivity to nitric oxide or their smaller baseline diameters. POP-FMD was associated with light physical activity levels in the pooled sample.

Impact of catheterization on shear-mediated arterial dilation in healthy young men

Purpose Animal studies have shown that endothelial denudation abolishes vasodilation in response to increased shear stress. Interestingly, shear-mediated dilation has been reported to be reduced, but not abolished, in coronary artery disease (CAD) patients following catheterization. However, it is not known whether this resulted from a priori endothelial dysfunction in this diseased population. In this study, we evaluated shear-mediated dilation following catheterization in healthy young men. Methods Twenty-six (age: 24.4 ± 3.8 years, BMI: 24.3 ± 2.8 kg m−2, VO2peak: 50.5 ± 8.8 ml/kg/min) healthy males underwent unilateral transradial catheterization. Shear-mediated dilation of both radial arteries was measured using flow-mediated dilation (FMD) pre-, and 7 days post-catheterization. Results FMD was reduced in the catheterized arm [9.3 ± 4.1% to 4.3 ± 4.1% (P < 0.001)] post-catheterization, whereas no change was observed in the control arm [8.4 ± 3.8% to 7.3 ± 3.8% (P = 0.168)]. FMD was completely abolished in the catheterized arm in five participants. Baseline diameter (P = 0.001) and peak diameter during FMD (P = 0.035) were increased in the catheterized arm 7 days post-catheterization (baseline: 2.3 ± 0.3 to 2.6 ± 0.2 mm, P < 0.001, peak: 2.5 ± 0.3 to 2.7 ± 0.3 mm, P = 0.001), with no change in the control arm (baseline: 2.3 ± 0.3 to 2.3 ± 0.3 mm, P = 0.288, peak: 2.5 ± 0.3 to 2.5 ± 0.3 mm, P = 0.608). Conclusion This is the first study in young healthy individuals with intact a priori endothelial function to provide evidence of impaired shear-mediated dilation following catheterization. When combined with earlier studies in CAD patients, our data suggest the catheterization impairs artery function in humans.

Baseline Diameter of the Inferior Vena Cava Measured with Sonography in Euvolemic Children and its Relationship to Somatic Variables

Purpose To determine normative data for the inferior vena cava (VCI) diameter in euvolemic children and its correlation with different somatic parameters in a pediatric population at one center in Europe. Materials and Methods This prospective observational study enrolled healthy children aged 4 weeks to 18y that visited our outpatient clinic. Weight, height, body surface area, and age were recorded. The children were grouped according to weight, as follows (80 children/group): < 10 kg, 10–19.9 kg, 20–29.9 kg, 30–59.9 kg, and 60–90 kg. Children were placed in a supine position and, during quiet respiration, the maximum and minimum VCI diameters were measured with M-mode ultrasonography. The collapsibility index (CI) was also automatically calculated for each subject: CI = [VCI maximum (expiratory) diameter – VCI minimum (inspiratory) diameter]/VCI maximum (expiratory) diameter. Results From May 2016 through November 2018 we retrieved data for 415 children that underwent VCI diameter evaluations. 400 children were included (mean age: 7.8y ± 5.8, mean weight: 32 kg ± 24.4, 46 % girls). The VCImax and the VCImin were significantly correlated with age (r = 0.867, p < 0.001, r = 0.797, p < 0.001), height (r = 0.840, p < 0.001, r = 0.772, p < 0.001), weight (r = 0.858, p < 0.001, r = 0.809, p < 0.001), and BSA (r = 0.878, p < 0.001, r = 0.817, p < 0.001). Correlations between the CI and age, weight, height, and BSA were not statistically significant. Conclusion This prospective study provided reference values for sonographic measurements of VCI diameters in euvolemic children and might greatly assist in assessing fluid status in sick children.

Pilot Study: The Effect of Acute 5-Day Creatine Supplementation on Macrovascular Endothelial Function in Older Adults

Objectives Cardiovascular disease (CVD) remains the leading cause of mortality in the United States, and aging is a primary risk factor for CVD events. Dietary creatine supplementation has been used to alleviate age-related health deteriorations, and has been shown to reduce sarcopenia, improve cognition and decrease reactive oxygen species in older adults. There is scarce information, however, regarding the use of creatine to improve vascular function. Therefore, the primary aim of this pilot study was to determine the effect of creatine on vascular function in older adults. Methods Four older adults (66 ± 8.3 years) participated in this pilot study, with four young adults (27 ± 2.9 years) serving as a comparator. Participants reported for their baseline visit, and completed basic anthropometrics and resting hemodynamic testing. Brachial artery flow mediated dilation (FMD) was used to assess macrovascular endothelial function following 5-minutes of occlusion. Resting and peak brachial artery diameters were assessed using edge detection software, and FMD % change (FMD%) was determined utilizing the following equation: [(peak diameter – baseline diameter)/baseline diameter] * 100. Participants were then given creatine monohydrate to consume over the following 5 days (4 × 5 g/day), before returning to repeat all assessments. A two-way ANOVA statistical analysis was performed using SPSS software, and significance was accepted at P ≤ 0.05. Results No statistically significant changes were seen in FMD%. However, mean delta (Δ) change for groups did show a greater improvement in FMD% in old vs. young (Δ2.44 ± 1.78% vs. −.82 ± 3.09%) and estimated marginal means of FMD showed a positive change in FMD% in older adults but not in younger. Furthermore, 100% of older adults showed improvement following creatine, whereas only 50% of young adults showed (minimal) improvement. Conclusions Although there were no significant changes identified, this may be due to the small sample size not being sufficient to detect an interaction effect. The improvements seen for each older adult could still be considered physiologically significant for vascular health, and future study of additional participants may result in significant benefits and expand the use of creatine to improve vascular health. Funding Sources No grants or Funding Sources were used for this pilot study.