Circulating High Mobility Group Box-1 Does Not Predict Pulmonary Arterial Hypertension in Children with Congenital Heart Disease: A Prospective Cohort Study.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a devastating complication of pediatric congenital heart disease (CHD). A recent study has identified the protein high mobility group box-1 (HMGB1) as a diagnostic tool in adults with CHD-associated PAH. HMGB1 levels in adults with CHD-associated PAH correlated with mean pulmonary artery pressure and pulmonary vascular resistance, and HGMB1 levels fell in response to sildenafil therapy. We wanted to assess if HGMB1 was a biomarker of pediatric CHD-PAH. DESIGN: Prospective cohort study. SETTING: Quaternary pediatric academic hospital PARTICIPANTS: Children ≤18 years with CHD with and without known pulmonary hypertension. Controls were children undergoing dental or urologic surgery with no known heart disease. INTERVENTIONS: Pulmonary hemodynamics, echocardiographic assessment, and biomarker measurement. Controls had biomarker measurement only. MEASUREMENTS AND MAIN RESULTS: Patients with CHD-PAH had mean pulmonary vascular resistance index of 10 Wood units/m2. Neither HGMB1 nor N-terminal pro-brain-type natriuretic peptide levels were significantly different between the groups. Neither marker correlated with pulmonary hypertension. CONCLUSIONS: Unlike in adults, HGMB1 is not a biomarker of PAH in pediatric CHD. Further work will continue to explore for biomarkers for this high-risk population.

Flow reduction due to arterial catheterization during stroke treatment - A computational study using a distributed compartment model.

The effectiveness of various stroke treatments depends on the anatomical variability of the cerebral vasculature, particularly the collateral blood vessel network. Collaterals at the level of the Circle of Willis and distal collaterals, such as the leptomeningeal arteries, serve as alternative avenues of flow when the primary pathway is obstructed during an ischemic stroke. Stroke treatment typically involves catheterization of the primary pathway, and the potential risk of further flow reduction to the affected brain area during this treatment has not been previously investigated. To address this clinical question, we derived the lumped parameters for catheterized blood vessels and implemented a corresponding distributed compartment (0D) model. This 0D model was validated against an experimental model and benchmark test cases solved using a 1D model. Additionally, we compared various off-center catheter trajectories modeled using a 3D solver to this 0D model. The differences between them were minimal, validating the simplifying assumption of the central catheter placement in the 0D model. The 0D model was then used to simulate blood flows in realistic cerebral arterial networks with different collateralization characteristics. Ischemic strokes were modeled by occlusion of the M1 segment of the middle cerebral artery in these networks. Catheters of different diameters were inserted up to the obstructed segment and flow alterations in the network were calculated. Results showed up to 45% maximum blood flow reduction in the affected brain region. These findings suggest that catheterization during stroke treatment may have a further detrimental effect for some patients with poor collateralization.

Collateral flow and pulsatility during large vessel occlusions: insights from a quantitative in vitro study.

Acute ischemic stroke caused by large vessel occlusions is being increasingly treated with neurovascular interventions. The hemodynamics within the collateral system of the circle of Willis (CoW) hemodynamics play a fundamental role in therapy success. However, transient in vivo data on pathological collateral flow during large vessel occlusions are not available. Moreover, there are no flow models that accurately simulate the hemodynamic conditions in the CoW during large vessel occlusions. We used a circulatory loop to generate highly reproducible cerebrovascular-like flows and pressures and used non-invasive flow visualization and high-resolution flow and pressure measurements to acquire detailed, time-dependent hemodynamics inside an anatomical phantom of the CoW. After calibrating a physiological reference case, we induced occlusions in the 1. middle cerebral artery, 2. terminal carotid artery, and 3. basilar artery; and measured the left posterior communicating artery flow. Mean arterial pressure and pulse pressure remained unchanged in the different occlusion cases compared to the physiological reference case, while total cerebral flow decreased by up to 19%. In all three occlusion cases, reversed flow was found in the left posterior communicating artery compared to the reference case with different flow magnitudes and pulsatility index values. The experimental results were compared with clinical findings, demonstrating the capability of this realistic cerebrovascular flow setup. This novel cerebrovascular flow setup opens the possibility for investigating different topics of neurovascular interventions under various clinical conditions in controlled preclinical laboratory studies.

Effects of single and bilateral limb immersion on systemic and cerebral hemodynamic responses to the cold pressor test.

The cold pressor test (CPT) involves cold water immersion of either the upper or lower limb(s) and elicits autonomic and hemodynamic increases via stimulation of pain and cutaneous thermoreceptors. It is unclear whether the choice of limb(s) in CPT studies differentially affects systemic and cerebral hemodynamic responses. Herein, we assessed systemic and cerebral hemodynamic and ventilatory responses to different CPT protocols of the hand (CPTH), foot (CPTF), or bilateral feet (CPTBF). We hypothesized CPTBF would elicit greatest physiological responses due to increased exposure area to the cold stimulus. Methods. Twenty-eight (14M;14F) healthy young adults [23.4 (SD: 2.4) years] participated in three 3-minute CPT protocols during a single visit. Mean arterial pressure (MAP), heart rate (HR), middle cerebral artery blood velocity (MCAv) and cerebrovascular conductance index, and end-tidal carbon dioxide (PETCO2), and pain perception were recorded throughout CPT protocols. Results. There was a time-CPT protocol interaction on systolic (p=0.02) and diastolic blood pressure (p<0.01), MAP (p<0.01), HR (p<0.001), presented as mean(SD). MCAv and cerebrovascular conductance index did not change with CPTs. Peak delta HR from baseline occurred in CPTBF (Δ13.6(15.5)BPM) compared to CPTH (Δ4.85(12.6)BPM; p=0.01) and CPTF (Δ4.04(13.3)BPM; p=0.02). Delta MAP was greater in CPTH (Δ12.3(7.95)mmHg) and CPTBF (Δ12.9(9.24)mmHg) compared to CPTF (Δ8.42(7.12)mmHg; p<0.01). Perceived pain was higher in CPTBF compared to single limb protocols (p≤0.01). Conclusion. Our findings suggest choice of limb(s) in CPT protocols affects systemic hemodynamic responses and should be considered when designing CPT studies.

Modulation of mechanosensitive genes during embryonic aortic arch development.

BACKGROUND: Early embryonic aortic arches (AA) are a dynamic vascular structures that are in the process of shaping into the great arteries of cardiovascular system. Previously, a time-lapsed mechanosensitive gene expression map was established for AA subject to altered mechanical loads in the avian embryo. To validate this map, we investigated effects on vascular microstructure and material properties following the perturbation of key genes using an in-house microvascular gene knockdown system. RESULTS: All siRNA vectors show a decrease in the expression intensity of desired genes with no significant differences between vectors. In TGFß3 knockdowns, we found a reduction in expression intensities of TGFß3 (≤76%) and its downstream targets such as ELN (≤99.6%), Fbn1 (≤60%), COL1 (≤52%) and COL3 (≤86%) and an increase of diameter in the left AA (23%). MMP2 knockdown also reduced expression levels in MMP2 (≤30%) and a 6-fold increase in its downstream target COL3 with a decrease in stiffness of the AA wall and an increase in the diameter of the AA (55%). These in vivo measurements were confirmed using immunohistochemistry, western blotting and a computational growth model of the vascular extracellular matrix (ECM). CONCLUSIONS: Localized spatial genetic modification of the aortic arch region governs the vascular phenotype and ECM composition of the embryo and can be integrated with mechanically-induced congenital heart disease models.

Quantification of morpho-hemodynamic changes in unruptured intracranial aneurysms with irregular pulsation during the cardiac cycle using 4D-CTA.

Background and purpose: Previous studies predicting the rupture risk of intracranial aneurysms (IAs) have predominantly utilized static imaging data, overlooking the dynamic blood flow and biomechanical properties of the aneurysm wall. Irregular pulsation detected by 4D-CTA is a potential predictor of aneurysm rupture, albeit with uncertain clinical significance. This study aimed to analyze the changes in morpho-hemodynamic characteristics of IAs during the cardiac cycle to elucidate the dynamic changes and the associated hemodynamic mechanisms. Methods: A retrospective review was conducted on the 4D-CTA data of IA patients between January 2017 and September 2019. R-R intervals were segmented into 20-time phases, reconstructing 20 CT datasets to identify irregular pulsation and extract 3D aneurysm models. Computational fluid dynamics (CFD) simulations analyzed hemodynamic parameters such as oscillatory shear index (OSI) and relative residence time (RRT). Changes in morpho-hemodynamic characteristics were quantified in terms of the absolute change (parameter*) and relative change rate (parameter%). Rupture risk was assessed using the rupture resemblance model (RRS). Results: Eleven UIAs from 10 patients were finally included, with five aneurysms showing irregular pulsation (45.45%). No significant differences in morpho-hemodynamic characteristics were observed between aneurysms with or without irregular pulsation. More remarkable changes in aneurysm size (size*: 0.59 ± 0.14 mm vs. 0.32 ± 0.12 mm, p = 0.010; size%: 10.49% ± 1.43% vs. 3.95% ± 1.79%, p < 0.001), volume (volume%: 13.72% vs. 6.39%, p = 0.009), OSI (OSI*: 0.02 ± 0.01 vs. 0.004 ± 0.005, p = 0.004; OSI%: 200% vs. 12.50%, p = 0.004) and RRT (RRT%: 97.14% vs. 43.95, p = 0.052) over the cardiac cycle were significantly linked to irregular pulsation. Aneurysms with irregular pulsation demonstrated a more unfavorable hemodynamic environment during the cardiac cycle, irrespective of the predicted rupture risk. Furthermore, irregular pulsation at the aneurysm dome exhibited higher hemodynamic instability than at the sidewall. Conclusion: Irregular pulsation may indicate hemodynamic instability within the aneurysm, leading to an increased rupture risk in the area where irregular pulsation occurs. This proof-of-concept study could enhance understanding of dynamic changes in UIAs during the cardiac cycle and the underlying hemodynamic mechanisms.

[4D flow MRI: value and clinical perspectives in patients with pathology of the heart and great vessels (part 2): A review].

The study of blood flow is becoming a new trend in cardiology and cardiovascular surgery. Based on the literature and our own data, a review is presented on the use of 4D flow in diseases of the heart and blood vessels. The main state of the question about the features of the application of the technique in various pathologies of the cardiovascular system is described in detail, the priorities, limitations and promising directions of the technique application are considered taking into account the goals of practical medicine. The review consists of two parts. The first is devoted to general issues, limitations of the technique, and issues of 4D flow mapping in patients with lesions of the great vessels. In the second part, the emphasis is on the use of 4D flow MRI in the study of intraventricular blood flow and the application of the technique in congenital heart and vascular diseases.

Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial.

BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. METHODS: In this secondary analysis from the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial, 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P=0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m2 [95% CI, 0.003-0.11] P=0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P=0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P=0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P=0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P=0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P<0.001). CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947.

Correlation of Apo B/A1 ratio with hemodynamics and hearing impairment degree in elderly patients with sudden sensorineural hearing loss.

Objective: To investigate the correlation of apolipoprotein B/A1 (Apo B/A1) ratio with hemodynamics and degree of hearing impairment in elderly patients with sudden sensorineural hearing loss (SSNHL). Methods: A total of 82 elderly patients with SSNHL diagnosed and treated in our hospital from July 2019 to September 2022 were retrospectively selected as the research group. The patients were divided into the mild group (22 cases), the moderate group (45 cases), and the severe group (15 cases) according to the degree of hearing impairment. 82 elderly people who underwent physical examination in our hospital during the same period were selected as the control group. The ApoB/A1 ratio and hemodynamic [whole blood low-shear viscosity (LSV), whole blood high-shear viscosity (HSV) and plasma viscosity (PV)] were measured in the two groups. The correlation of ApoB/A1 ratio with hemodynamics and degree of hearing impairment was analyzed. The predictive value of ApoB/A1 ratio and hemodynamics for the severity of SSNHL in elderly patients was analyzed. Results: Compared with the control group, the ApoB/A1 ratio, and the levels of LSV, HSV and PV were higher in the research group (P < 0.001). The ApoB/A1 ratio and content of LSV, HSV and PV in the moderate group were significantly increased compared with these in the mild group (P < 0.05). Compared with the moderate group, the ApoB/A1 ratio and the levels of LSV, HSV and PV in the severe group were significantly increased (P < 0.05). Pearson correlation analysis showed that ApoB/A1 was positively correlated with LSV, HSV and PV (r = 0.303, 0.312, 0.228, P < 0.01). Logistic regression analysis showed that the ApoB/A1 ratio, LSV, HSV and PV levels were independent risk factors for the degree of hearing impairment in elderly patients with SSNHL (P < 0.05). The area under the curve (AUC) of ApoB/A1, LSV, HSV and PV for predicting the severity of SSNHL in elderly patients was 0.701, 0.817, 0.838, and 0.765, respectively. The AUC of combined prediction was 0.926, the sensitivity was 86.67 %, and the specificity was 90.06 %. The sensitivity and specificity of combined detection were higher than those of single detection. Conclusion: The contents of ApoB/A1, HSV, LSV and PV were significantly increased in elderly patients with SSNHL, and their levels are significantly related to the degree of hearing impairment. The combined detection has high value in evaluating the severity of the disease.

Left and Right Ventricular Hemodynamic Response After Transcatheter Mitral Valve Replacement.

Background: Transcatheter mitral valve replacement (TMVR) represents a novel treatment option for patients with mitral regurgitation (MR), but little is known about the hemodynamic impact of MR elimination following TMVR. We sought to investigate the hemodynamic impact of TMVR on left ventricular (LV) and right ventricular (RV) function using noninvasive pressure-volume loops. Methods: All consecutive patients undergoing TMVR with dedicated devices between May 2016 and August 2022 were enrolled. The end-diastolic and end-systolic pressure-volume relationships were estimated from 26 patients using single-beat echocardiographic measurements at baseline and after TMVR at discharge. RV function was assessed by RV-pulmonary artery (PA) coupling and RV fractional area change. One-year follow-up was available for 19 patients. The prognostic impact of calculated end-diastolic volume at an end-diastolic pressure of 20 mmHg (VPed20) reduction was assessed by Cox regression. Results: A total of 26 patients (77.0 years [interquartile range 73.9-80.1], N = 17 [65.4%] male) with successful TMVR were included (secondary MR [N = 21, 80.8%]; median LV ejection fraction was 37.0% [interquartile range 30.7-50.7]). At discharge, a decrease in VPed20 (p < 0.001) indicating leftward shift of end-diastolic pressure-volume relationship, and an increase of the end-systolic elastance slope (p = 0.007) were observed after TMVR. No changes were observed for RV-PA coupling (p = 0.19) and RV fractional area change (p = 0.22). At 1-year follow-up, LV contractility (end-systolic elastance) and RV-PA coupling remained stable. Vped20 reduction at discharge was significantly associated with 1-year all-cause mortality or heart failure hospitalization (hazard ratio 0.16, 95% CI 0.04-0.71, p = 0.016). Conclusions: Noninvasive assessment of pressure-volume loops demonstrated early LV reverse remodeling and improved LV contractility, while RV performance was preserved. These results indicate the potential prognostic impact of complete MR elimination after TMVR.

Analysis of the relationship between VEGF, NLRP3 inflammatory complex, EPO levels, and ocular hemodynamics in patients with primary open-angle glaucoma.

OBJECTIVE: Our study aimed to investigate the relationship between vascular endothelial growth factor (VEGF), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory complex, erythropoietin (EPO) levels, and ocular hemodynamics in patients diagnosed with primary open-angle glaucoma (POAG). METHODS: This is a prospective observational study. Patients diagnosed with POAG at The Sixth Hospital of Wuhan hospital between November 2022 and February 2023were enrolled.The patients were categorized into three groups based on the average visual field defect (mean deviation, MD) value: severe injury group (MD > 12 dB, 93 cases), moderate injury group (7 ≤ MD ≤ 12 dB, 89 cases), and mild injury group (MD < 7 dB, 85 cases). The levels of VEGF, NLRP3 inflammatory complex, EPO, and ocular hemodynamics were compared among the groups. Furthermore, the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG was analyzed using Pearson correlation analysis. After adjusting for confounding factors such as age and gender, multivariate Logistic regression analysis was performed with the ocular hemodynamics indexes being used as dependent variables, and VEGF, NLRP3, ASC, Caspase-1, and EPO being used as independent variables. RESULTS: A total of267 patients with POAG were enrolled. There were no significant differences in sex, age, body mass index, systolic blood pressure, diastolic blood pressure, smoking, alcohol consumption, and blood glucose between the two groups (P > 0.05). The levels of NLRP3, ASC, Caspase-1, and EPO in the severe and moderate injury groups were higher than those in the mild injury group, whereas the VEGF levels were lower in the severe and moderate groups compared to the mild group, showing significant differences (P < 0.05). The severe group exhibited higher levels of NLRP3, ASC, Caspase-1, and EPO than the moderate group, while the VEGF levels were lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). The peak systolic velocity(PSV) and resistance index (RI) were higher in the severe and moderate groups than in the mild group, whereas the EDV was significantly lower in the severe and moderate groups compared to the mild group (P < 0.05). The severe group exhibited higher PSV and RI values compared to the moderate group, while the EDV was lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). Pearson correlation analysis was performed to examine the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG. VEGF, NLRP3, ASC, Caspase-1, and EPO showed positive correlations with PSV and RI, and negative correlations with EDV in patients with POAG. Regression analysis showed that VEGF, NLRP3, ASC, Caspase-1 and EPO were significantly correlated with ocular hemodynamics in POAG (all P < 0.001). CONCLUSION: We demonstrated that the levels of VEGF, NLRP3 inflammatory complex, and EPO were highly associated with ocular hemodynamics in patients diagnosed with POAG.

Association of norepinephrine with pressure ulcer development in critically ill patients with COVID-19-related acute respiratory distress syndrome: A dose-response analysis.

OBJECTIVES: To investigate the correlation between varying doses of norepinephrine (NE) and the incidence of pressure injuries (PIs) in COVID-19 patients in intensive care units (ICUs). DESIGN: A retrospective multicenter study was conducted on 1,078 COVID-19 patients admitted to ICUs with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. The research spanned from March 2020 to April 2021 across five university-affiliated hospitals in Iran. Univariate and multivariate binary logistic regression analyses, along with linear and non-linear dose-response assessments, were utilized to evaluate the relationship between NE dosages and the probability of PI development. FINDINGS: The multivariate analysis revealed a significant association between higher doses of NE administered over 24 h (OR: 1.832, 95 % CI: 1.218-2.754, P=0.004) and cumulative doses (OR: 1.408, 95 % CI: 1.204-1.975, P=0.048) with the occurrence of PIs. Moreover, patients receiving high NE doses had a nearly fourfold increased risk of developing PIs, regardless of PIs stage, compared to those on low or moderate doses (>15 µg/min vs. ≤ 15 µg/min; OR: 4.401, 95 % CI: 3.339-5.801, P=0.001). Although the linear dose-response analysis did not show a significant correlation between NE doses (µg/min) and PI development (P>0.05), the non-linear analysis indicated that NE doses ≤ 9 µg/min were associated with a reduced risk of PI development. CONCLUSION: Maintaining NE infusion within the range of 1-9 µg/min appears to be most effective in reducing the likelihood of PIs in ICU patients with COVID-19. Lower NE doses (≤9 µg/min) were associated with a lower risk of PI development, suggesting that factors beyond NE dosage or the use of other vasopressors may play a crucial role in PI formation in this patient cohort. IMPLICATIONS FOR CLINICAL PRACTICE: Rather than suggesting a specific threshold, clinicians should consider further studies to determine the optimal dose that balances microvascular perfusion and patient outcomes. It is crucial to comprehensively evaluate additional factors and selectively use vasopressors. Individualized care, including regular monitoring and personalized treatment plans, is essential for achieving the best outcomes in this patient population.

Comparison of Hemodynamic Changes During Acupuncture Stimulation in Supine or Sitting Position in Human Subjects.

Objective: Position change influences acupuncture-induced heart rate (HR) reduction, which is caused by a somatoautonomic reflex. However, the influences of position on the hemodynamic system-including HR, blood pressure (BP), and cardiac output (CO) during acupuncture-remains unclear. This study comprehensively compared cardiovascular changes induced by acupuncture in human beings supine and sitting positions. Materials and Methods: Comprehensive measurements were made of 30 healthy male volunteers, including HR, stroke volume (SV), and BP, in a supine posture for 15 minutes. Manual acupuncture stimulation was performed at the left LI-10 point for 1 minute. After at least 1 week, the same protocol was performed with all subjects in a sitting position. Results: Preacupuncture, there were increases in HR and BP, and decreases in SV and CO in the sitting position, compared with the supine position. Acupuncture stimulation induced HR reduction more when the subjects were in the sitting position, compared with them in the supine position. Acupuncture-induced increase in SV and decrease in diastolic BP were not different in either position. In the sitting position, CO decreased during acupuncture, compared with preacupuncture; this did not occur in the supine position. Conclusions: The effects of acupuncture on the hemodynamic system changed between the supine and sitting positions in healthy young men. Autonomic nervous-tone influences acupuncture-induced cardiovascular changes through physiologic responses, including the somatoautonomic reflex and the baroreflex.

Unlocking potential of oxytocin: improving intracranial lymphatic drainage for Alzheimer's disease treatment.

Background: The impediment to ß-amyloid (Aß) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aß from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.

Pleural Effusion and Invasive Hemodynamic Measurements in Advanced Heart Failure.

BACKGROUND: Pleural effusion is present in 50% to 80% of patients with acute heart failure, depending on image modality. We aim to describe the association between the presence and size of pleural effusion and central hemodynamics, including pulmonary capillary wedge pressure (PCWP) in an advanced heart failure population. METHODS: An observational, cross-sectional study in a cohort of patients with advanced heart failure (left ventricular ejection fraction ≤45%) who underwent right heart catheterization at The Department of Cardiology at Copenhagen University Hospital, Rigshospitalet, Denmark, between January 1, 2002 and October 31, 2020. The presence and size of pleural effusion were determined by a semiquantitative score of chest x-rays or computed tomography scans performed within 2 days of right heart catheterization. RESULTS: In 346 patients (50±13 years; 78% males) with median left ventricular ejection fraction of 20% (15-25), we identified 162 (47%) with pleural effusion. The pleural effusion size was medium in 38 (24%) and large in 30 (19%). Patients with pleural effusion had a 4.3 mm Hg (2.5-6.1) higher PCWP and 2.4 mm Hg (1.2-3.6) higher central venous pressure (P<0.001 for both). Patients with a medium/large pleural effusion had statistically significantly higher filling pressures than patients with a small effusion. Higher PCWP (odds ratio [OR], 1.06 [1.03-1.10]) and central venous pressure (OR, 1.09 [1.05-1.15]) were associated with pleural effusion in multivariable logistic regression adjusted for age, sex, and heart failure medications (P<0.001 for both). In a subgroup of 204 (63%) patients with serum albumin data, PCWP (OR, 1.06 [1.01-1.11]; P=0.032), central venous pressure (OR, 1.14 [1.06-1.23]; P<0.001) and serum albumin level (OR, 0.89 [0.83-0.95]; P<0.001) were independently associated with the presence of a medium/large-sized pleural effusion. CONCLUSIONS: In patients with left ventricular ejection fraction ≤45% undergoing right heart catheterization as part of advanced heart failure work-up, pleural effusion was associated with higher PCWP and central venous pressure and lower serum albumin.

Congestion/decongestion in heart failure: what does it mean, how do we assess it, and what are we missing?-is there utility in measuring volume?

Clinical congestion remains a major cause of hospitalization and re-hospitalizations in patients with chronic heart failure (HF). Despite the high prevalence of this issue and clinical concern in HF practice, there is limited understanding of the complex pathophysiology relating to the "congestion" of congestive HF. There is no unifying definition or clear consensus on what is meant or implied by the term "congestion." Further, the discordance in study findings relating congestion to physical signs and symptoms of HF, cardiac hemodynamics, or metrics of weight change or fluid loss with diuretic therapy has not added clarity. In this review, these factors will be discussed to add perspective to this issue and consider the factors driving "congestion." There remains a need to better understand the roles of fluid retention promoting intravascular and interstitial compartment expansions, blood volume redistribution from venous reservoirs, altered venous structure and capacity, elevated cardiac filling pressure hemodynamics, and heterogeneous intravascular volume profiles (plasma volume and red blood cell mass) with a goal to help demystify "congestion" in HF. Further, this includes highlighting the importance of recognizing that congestion is not the result of a single pathway but a complex of responses some of which produce symptoms while others do not; yet, we confine these varied responses to the single and somewhat vague term "congestion."

Intracranial pressure-flow relationships in traumatic brain injury patients expose gaps in the tenets of models and pressure-oriented management.

Background: The protocols and therapeutic guidance established for treating traumatic brain injury (TBI) in neurointensive care focus on managing cerebral blood flow (CBF) and brain tissue oxygenation based on pressure signals. The decision support process relies on assumed relationships between cerebral perfusion pressure (CPP) and blood flow, pressure-flow relationships (PFRs), and shares this framework of assumptions with mathematical intracranial hemodynamics models. These foundational assumptions are difficult to verify, and their violation can impact clinical decision-making and model validity. Methods: A hypothesis- and model-driven method for verifying and understanding the foundational intracranial hemodynamic PFRs is developed and applied to a novel multi-modality monitoring dataset. Results: Model analysis of joint observations of CPP and CBF validates the standard PFR when autoregulatory processes are impaired as well as unmodelable cases dominated by autoregulation. However, it also identifies a dynamical regime -or behavior pattern-where the PFR assumptions are wrong in a precise, data-inferable way due to negative CPP-CBF coordination over long timescales. This regime is of both clinical and research interest: its dynamics are modelable under modified assumptions while its causal direction and mechanistic pathway remain unclear. Conclusion: Motivated by the understanding of mathematical physiology, the validity of the standard PFR can be assessed a) directly by analyzing pressure reactivity and mean flow indices (PRx and Mx) or b) indirectly through the relationship between CBF and other clinical observables. This approach could potentially help to personalize TBI care by considering intracranial pressure and CPP in relation to other data, particularly CBF. The analysis suggests a threshold using clinical indices of autoregulation jointly generalizes independently set indicators to assess CA functionality. These results support the use of increasingly data-rich environments to develop more robust hybrid physiological-machine learning models.

Network Topology of Wing Veins in Hawaiian Flies Mitigates Allometric Dilemma.

Specific Hawaiian fruit flies have an extra crossvein (ECV) in the wing vein network which connects contiguously with another crossvein and forms a unique cruciform topology. These flies are distinguished by their large wings and their allometrically small vein diameters compared to those of typical fruit flies. Small vein diameters may increase frictional energy loss during internal blood transport, although they lead to an improvement in the wing's moment of inertia. Our hypothesis was that the ECV's presence would reduce the hydraulic resistance of the entire vein network. To investigate the hemodynamic effects of its presence, the flow rate of blood and frictional pressure loss within the vein networks was simulated by modeling them as hydraulic circuits. The results showed a 3.1% reduction in pressure loss owing to the network topology created by the presence of the ECV. This vein and its contiguous crossvein diverted part of the blood from the wing veins topologically parallel to them, reducing the pressure loss in these bypassed veins. The contiguity of the ECV to the other crossvein provided the shortest blood transfer route and lowest pressure drop between these crossveins. The results suggest that the presence of the ECV may counterbalance the heightened resistance caused by constricted veins.

Effects of weightlessness on the cardiovascular system: a systematic review and meta-analysis.

Background: The microgravity environment has a direct impact on the cardiovascular system due to the fluid shift and weightlessness that results in cardiac dysfunction, vascular remodeling, and altered Cardiovascular autonomic modulation (CAM), deconditioning and poor performance on space activities, ultimately endangering the health of astronauts. Objective: This study aimed to identify the acute and chronic effects of microgravity and Earth analogues on cardiovascular anatomy and function and CAM. Methods: CINAHL, Cochrane Library, Scopus, Science Direct, PubMed, and Web of Science databases were searched. Outcomes were grouped into cardiovascular anatomic, functional, and autonomic alterations, and vascular remodeling. Studies were categorized as Spaceflight (SF), Chronic Simulation (CS), or Acute Simulation (AS) based on the weightlessness conditions. Meta-analysis was performed for the most frequent outcomes. Weightlessness and control groups were compared. Results: 62 articles were included with a total of 963 participants involved. The meta-analysis showed that heart rate increased in SF [Mean difference (MD) = 3.44; p = 0.01] and in CS (MD = 4.98; p < 0.0001), whereas cardiac output and stroke volume decreased in CS (MD = -0.49; p = 0.03; and MD = -12.95; p < 0.0001, respectively), and systolic arterial pressure decreased in AS (MD = -5.20; p = 0.03). According to the qualitative synthesis, jugular vein cross-sectional area (CSA) and volume were greater in all conditions, and SF had increased carotid artery CSA. Heart rate variability and baroreflex sensitivity, in general, decreased in SF and CS, whereas both increased in AS. Conclusion: This review indicates that weightlessness impairs the health of astronauts during and after spaceflight, similarly to the effects of aging and immobility, potentially increasing the risk of cardiovascular diseases. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020215515.