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Heart failure is a leading cause of morbidity and mortality 1 , 2 . Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion 3 – 8 . Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect 9 , 10 . Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure. Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

ObjectiveTo investigate the effect of spontaneous breathing on venous return in term infants during delayed cord clamping at birth.MethodsEchocardiographic ultrasound recordings were obtained directly after birth in healthy term-born infants. A subcostal view was used to obtain an optimal view of the inferior vena cava (IVC) entering the right atrium, including both the ductus venosus (DV) and the hepatic vein (HV). Colour Doppler was used to assess flow direction and flow velocity. Recordings continued until the umbilical cord was clamped and were stored in digital format for offline analyses.ResultsUltrasound recordings were obtained in 15 infants, with a median (IQR) gestational age of 39.6 (39.0–40.9) weeks and a birth weight of 3560 (3195–4205) g. Flow was observed to be antegrade in the DV and HV in 98% and 82% of inspirations, respectively, with flow velocity increasing in 74% of inspirations. Retrograde flow in the DV was observed sporadically and only occurred during expiration. Collapse of the IVC occurred during 58% of inspirations and all occurred caudal to the DV inlet (100%).ConclusionSpontaneous breathing was associated with collapse of the IVC and increased antegrade DV and HV flow velocity during inspiration. Therefore, inspiration appears to preferentially direct blood flow from the DV into the right atrium. This indicates that inspiration could be a factor driving placental transfusion in infants.

Pulse wave attenuation characteristics reflect compliance and resistance properties of the vessel wall as well as initial pulse generation factors. Recently, it has become possible to measure and map the retinal vessel wall pulse wave amplitudes. Predictable pulse wave amplitude distribution may allow inferences to be made concerning vascular compliance and resistance. Twenty-eight eyes from sixteen subjects (8 male and 8 female) were examined using modified retinal photoplethysmography with simultaneous ophthalmodynamometry. This allowed the assessment of vessel wall pulsation amplitudes under a dynamic range of intraocular pressures. Pulse amplitudes were calculated using harmonic regression analysis. The pulse wave attenuation was measured under different ranges of ophthalmodynamometric force (ODF) as a function of distance along the vessel (VDist), which in turn was calculated in disc diameters (DD) from the center of the optic disc. A linear mixed-effects model with randomized slopes and intercepts was used to estimate the correlations between the logarithmically transformed harmonic regression wave amplitude (HRWa) and the Fourier trigonometric coefficients with the predictors (VDist and ODF). The retinal venous harmonic regression wave attenuation (coefficient value±standard error) -0.40±0.065/DD, (p-value < 0.00001, 95% confidence interval (CI) -0.53 to -0.27), which was approximately twice that of the arterial -0.17±0.048/DD, (p-value < 0.0004, 95% CI = -0.27 to -0.08). There was a positive correlation between attenuation of the harmonic regression wave and ophthalmodynamometric force in both vascular systems. The attenuation of all but the sine coefficient of the second Fourier harmonic (bn2) achieved statistical significance in the correlation with VDist. The cosine coefficient of the first Fourier harmonic an1 was the only coefficient to achieve statistical significance in the correlation with the predictors VDist and ODF in both vascular systems. The an1 coefficient value in the correlation with VDist was -3.79±0.78 and -1.269±0.37 (p < 0.0006), while this coefficient value in the correlation with ODF was 0.026±0.0099 and 0.009±0.04 (p < 0.01) in both the retinal veins and arteries respectively. The predictable attenuation characteristics in normal subjects suggest that this technique may allow the non-invasive quantification of retinal vascular compliance and other hemodynamic parameters.

Aberrations in flow in the cerebral venous outflow tract (CVOT) have been implicated as the cause of several pathologic conditions including idiopathic intracranial hypertension (IIH), multiple sclerosis (MS), and pulsatile tinnitus (PT). The advent of 4D flow magnetic resonance imaging (4D-flow MRI) has recently allowed researchers to evaluate blood flow patterns in the arterial structures with great success. We utilized similar imaging techniques and found several distinct flow characteristics in the CVOT of subjects with and without lumenal irregularities. We present the flow patterns of 8 out of 38 subjects who have varying heights of the internal jugular bulb and varying lumenal irregularities including stenosis and diverticulum. In the internal jugular vein (IJV) with an elevated jugular bulb (JB), 4Dflow MRI revealed a characteristic spiral flow that was dependent on the level of JB elevation. Vortical flow was also observed in the diverticula of the venous sinuses and IJV. The diversity of flow complexity in the CVOT illustrates the potential importance of hemodynamic investigations in elucidating venous pathologies.

Veins are often subjected to torsion and twisted veins can hinder and disrupt normal blood flow but their mechanical behavior under torsion is poorly understood. The objective of this study was to investigate the twist deformation and buckling behavior of veins under torsion. Twist buckling tests were performed on porcine internal jugular veins (IJVs) and human great saphenous veins (GSVs) at various axial stretch ratio and lumen pressure conditions to determine their critical buckling torques and critical buckling twist angles. The mechanical behavior under torsion was characterized using a two-fiber strain energy density function and the buckling behavior was then simulated using finite element analysis. Our results demonstrated that twist buckling occurred in all veins under excessive torque characterized by a sudden kink formation. The critical buckling torque increased significantly with increasing lumen pressure for both porcine IJV and human GSV. But lumen pressure and axial stretch had little effect on the critical twist angle. The human GSVs are stiffer than the porcine IJVs. Finite element simulations captured the buckling behavior for individual veins under simultaneous extension, inflation, and torsion with strong correlation between predicted critical buckling torques and experimental data (R2=0.96). We conclude that veins can buckle under torsion loading and the lumen pressure significantly affects the critical buckling torque. These results improve our understanding of vein twist behavior and help identify key factors associated in the formation of twisted veins.

Background Older patients with cardiovascular disease often experience frailty and sarcopenia. We evaluated whether a reduced blood flow in the splenic and portal vein is associated with frailty and sarcopenia in older patients with cardiovascular disease. Methods Blood flow in the splenic and portal vein was evaluated using EPIQ7 (Philips) in older patients (aged ≥ 65 years, 123 patients) with cardiovascular disease, who visited the frailty outpatient clinic. Frailty was assessed using the Japanese version of Cardiovascular Health Study (J-CHS) criteria and the Kihon Checklist (KCL), while sarcopenia was assessed using the Asian Working Group of Sarcopenia 2019 criteria. Results The mean age of the patients was 81.6 ± 6.6 years (42.3% female). Frailty was observed in 34.2% of patients using the J-CHS criteria and 36.9% using the KCL criteria, while severe sarcopenia was identified in 20.2% of patients. In the KCL criteria, the splenic venous flow decreased with the severity of frailty (248.3 ± 148.4, 202.1 ± 177.9, 139.2 ± 81.1 mL/min, P  = 0.007), Additionally, the splenic venous flow was significantly lower in frail patients than in robust patients ( P  = 0.006). This association remained significant even after adjusting for confounding factors such as age, sex, body mass index, habitual drinking, smoking history, diabetes, dyslipidemia, hypertension, systolic blood pressure, atrial fibrillation, heart failure, and history of stroke ( P  = 0.039). In a parallel analysis, the splenic venous flow was remarkably decreased in patients with sarcopenia (232.0 ± 172.8 vs. 145.0 ± 91.9 mL/min, P  = 0.003); however, no significant relationship was found between the severity of frailty and splenic venous flow according to the J-CHS criteria ( P  = 0.159). Among the J-CHS criteria sub-items, the splenic venous flow was decreased in patients with a decreased appendicular skeletal muscle index (ASMI) (332.9 ± 41.6 vs. 98.5 ± 43.5 mL/min, P  = 0.005); however, there was no significant difference in the splenic venous flow between patients with and without decreased walking speed ( P  = 0.064) or reduced grip strength ( P  = 0.369). The portal venous flow was not significantly associated with frailty or sarcopenia. Conclusion In older patients with cardiovascular disease, a decreased splenic venous flow was observed in those with frailty by the KCL criteria, those with sarcopenia, and those with a decreased ASMI.

Venous thromboembolism is a significant complication after knee replacement. The short-term efficacy disparities between different types of graduated elastic compression stockings (GCS) among patients undergoing total/unicompartmental knee replacement remain unclear. The aim of the trial was to compare the efficacies on hemodynamics and morphology of femoral vein between two types of GCS, providing more evidence on GCS prophylaxis among patients undergoing total/unicompartmental knee replacement. In this single center, double-blind, parallel design, randomized trial, 141 adult patients who underwent selective, unilateral total/unicompartmental knee replacement operation for the first time were enrolled, with 71 were assigned to type A GCS and 70 to type B GCS, respectively. Compressed ultrasound of the lower extremity was conducted before the operation (without GCS, as preoperative baseline) and within 24 hours post operation (postoperative baseline , with GCS, and with GCS + ankle pump). The relative changes in TV and PV, as well as the diameter of the femoral vein in the healthy leg, were assessed both before and after GCS application following the knee replacement surgery. The median ages were 67.0 years in type A group and 68.0 years in type B group. All parameters of femoral vein were comparable between type A and type B GCSs. Compared with postoperative baseline, GCS + ankle pump significantly reduced femoral vein diameter and improved the TV in both GCS types; GCS and GCS + ankle pump also significantly increased the TV (median 1.2%, IQR -21.4% to 58.6%,  = 0.0384; median 14.0%, IQR -24.3% to 93.0%,  = 0.0019, respectively) in left leg, while not significant in right leg. The efficacies of two GCSs were comparable, and both were effective in improving velocity and morphology of femoral veins of the healthy legs among patients undergoing knee replacement, especially in improving TVs of femoral veins for left leg.

Purpose The aim of the study was to compare the kinetics responses of heart rate (HR), pulmonary ( V ˙ O 2pulm ), and muscular ( V ˙ O 2musc ) oxygen uptake during dynamic leg exercise across different body positions (−6°, 45°, and 75°). Methods Ten healthy individuals [six men, four women; age 23.4 ± 2.8 years; height 179.7 ± 8.3 cm; body mass 73 ± 12 kg (mean ± SD)] completed pseudo-random binary sequence (PRBS) work rate (WR) changes between 30 and 80 W in each posture. HR was measured beat-to-beat by echocardiogram and V ˙ O 2pulm by breath-by-breath gas exchange. V ˙ O 2musc kinetics were assessed by the procedure of Hoffmann et al. (Eur J Appl Physiol 113:1745–1754, 2013 ) applying a circulatory model and cross-correlation functions (CCF). Results For V ˙ O 2pulm kinetics significant differences between −6° (CCF-values: 0.292 ± 0.040) and 45° (0.256 ± 0.034; p  < 0.01; n  = 10) as well as between −6° and 75° (0.214 ± 0.057; p  < 0.05; n  = 10) were detected at lag ‘40 s’ of the CCF course as interaction effects (factors: Lag  ×  Posture ). HR and V ˙ O 2musc kinetics yield no significant differences across the postures. Conclusions The analysis of cardio-dynamic and respiratory kinetics, especially with an emphasis on muscular and cellular level, has to consider venous return and cardiac output distortions. Simplified observations of kinetics responses resulting in time constants and time delays only should be replaced by the time-series analysis for a more sophisticated evaluation. The results illustrate that isolated V ˙ O 2pulm measurements without cardio-dynamic influences may not represent the kinetics responses originally revealed at muscular level.

The superficial veins of the forelimb show high variability, both in man and in other primates, regarding the number of main venous trunks, their course, as well as the origin and location of openings. The distinction between two venous systems–the superficial and deep was made based on the relation of specific venous channels to the deep fascia; both groups of veins anastomose to each other through perforators piercing the deep fascia. In our work, we paid special attention to the organization of the venous system within the forelimb of the Anubis baboon (Papio anubis), as well as communications between the superficial and deep venous system. The main aim of the study was a detailed examination of the location of venous valves and perforating veins in forelimb of Anubis baboon. In the Anubis baboon, we observed the absence of the basilic vein. The main vessel within the forelimb, in the superficial venous system, was a well-developed cephalic vein. In all the cases, the cephalic vein opened into the external jugular vein. Also, in all of the examined specimens, there was an additional anastomosis connecting the cephalic and external jugular vein, i.e., persistent jugulocephalic vein located anterior to the clavicle. The venous vessels in the Anubis baboon were arranged in two main layers: superficial and deep, with both systems being connected by perforators located at the level of the carpus and cubital fossa. The number of venous valves within the cephalic vein was greater on the forearm the same as the mean intervalvular distance.

PurposeSuspension syndrome describes a potentially life-threatening event during passive suspension on a rope. The pathophysiological mechanism is not fully understood and optimal treatment unknown. We aimed to elucidate the pathophysiology and to give treatment recommendations.MethodsIn this experimental, randomized crossover trial, 20 healthy volunteers were suspended in a sit harness for a maximum of 60 min, with and without prior climbing. Venous pooling was assessed by measuring the diameter of the superficial femoral vein (SFV), lower leg tissue oxygenation (StO2) and by determining localized bioelectrical impedance. Hemodynamic response was assessed by measuring heart rate, blood pressure, stroke volume, and left ventricular diameters. Signs and symptoms of pre-syncope were recorded.ResultsTwelve (30%) out of 40 tests were prematurely terminated due to pre-syncopal symptoms (mean 44.7 min, minimum 13.4, maximum 59.7). SFV diameter increased, StO2 and the capacitive resistance of the cells decreased indicating venous pooling. Heart rate and blood pressure did not change in participants without pre-syncope. In contrast, in participants experiencing pre-syncope, heart rate and blood pressure dropped immediately before the event. All symptoms dissolved and values returned to normal within 5 min with participants in a supine position.ConclusionsSudden pre-syncope during passive suspension in a harness was observed in 30% of the tests. Blood pools in the veins of the lower legs; however, a vagal mechanism finally leads to loss of consciousness. Time to pre-syncope is unpredictable and persons suspended on a rope should be rescued and put into a supine position as soon as possible.