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Purpose: Intravenous injections are a common invasive procedure for delivering fluids or medications. Although patients experience pain from needle insertion, this discomfort is often overlooked due to its short duration and perceived insignificance. This study aimed to assess the effect of applying cryotherapy and thermotherapy using a flexible thermoelectric device on relieving the pain caused by intravenous injections. Methods: This randomized controlled trial utilized the modified thermoelectric element (M-TEE) tourniquet, which improves heat and cold transfer through a flexible TEE. Participants were hospitalized adults who had an 18-gauge angiocatheter inserted for surgery. The M-TEE tourniquet was applied 10-12 cm above the injection site, providing thermotherapy (40°C-45°C) or cryotherapy (0°C-10°C) to the respective groups. The control group received no temperature treatment. Pain, peripheral oxygen saturation, pulse rate, and regional blood flow were measured. Post- injection, satisfaction surveys were conducted with participants and practitioners. Results: There was a significant difference in pain perception among the three groups (F = 3.38, p = .041), with the cryotherapy group reporting less pain than the control group (p = .036). Regional venous blood flow significantly increased during thermotherapy (F = 5.99, p = .004), although regional arterial flow remained unchanged. Participant satisfaction differed across groups (F = 3.26, p = .046), with higher satisfaction in the cryotherapy group than in the control group (p = .040). Nurses’ satisfaction also varied significantly (F = 24.14, p < .001) across the groups. Conclusion: The M-TEE tourniquet effectively reduces intravenous injection pain and increases patient and practitioner satisfaction, particularly with cryotherapy. [ABSTRACT FROM AUTHOR]

Despite the known interplay between blood flow and function, to our knowledge, there is currently no minimally invasive method to monitor diaphragm hemodynamics. We used contrast-enhanced ultrasound to quantify relative diaphragm blood flow (Q ˙ DIA) in humans and assessed the technique's efficacy and reliability during graded inspiratory pressure threshold loading. We hypothesized that: (1) Q ˙ DIA would linearly increase with pressure generation, and (2) that there would be good test-retest reliability and interanalyzer reproducibility. Can we validate what is, to our knowledge, the first minimally invasive method to measure relative diaphragm blood flow in humans? Quantitative contrast-enhanced ultrasound of the costal diaphragm was performed in healthy participants (10 male participants, 6 female participants; mean age 28 ± 5 years; BMI 22.8 ± 2.0 kg/m) during unloaded breathing and three stages of loaded breathing on two separate days. Gastric and esophageal balloon catheters measured transdiaphragmatic pressure. Ultrasonography was performed during a constant-rate IV infusion of lipid-stabilized microbubbles following each stage. Ultrasound images were acquired after a destruction-replenishment sequence and diaphragm specific time-intensity data were used to determine Q ˙ DIA by two individuals. Transdiaphragmatic pressure for unloaded and each loading stage were 15.2 ± 0.8, 26.1 ± 0.8, 34.6 ± 0.8, and 40.0 ± 0.8 percentage of the maximum, respectively. Q ˙ DIA increased with each stage of loading (3.1 ± 3.1, 6.9 ± 3.6, 11.0 ± 4.9, and 13.5 ± 5.4 acoustic units/s; P <.0001). The linear relationship between diaphragmatic flow and pressure was reproducible from day to day. Q ˙ DIA had good to excellent test-retest reliability (0.86 [0.77, 0.92]; P <.0001) and excellent interanalyzer reproducibility (0.93 [0.90, 0.95]; P <.0001) with minimal bias. Relative Q ˙ DIA measurements had valid physiological underpinnings, were reliable day-to-day, and were reproducible analyzer-to-analyzer. This study indicated that contrast-enhanced ultrasound is a viable, minimally invasive method for assessing costal Q ˙ DIA in humans and may provide a tool to monitor diaphragm hemodynamics in clinical settings. [Display omitted] [ABSTRACT FROM AUTHOR]

Prior studies of muscle blood flow and muscle-specific oxygen consumption have required invasive injection of dye and magnetic resonance imaging, respectively. Such measures have limited utility for continuous monitoring of the respiratory muscles. Frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy (FD-NIRS & DCS) can provide continuous surrogate measures of blood flow index (BFi) and metabolic rate of oxygen consumption (MRO2). This study aimed to validate sternocleidomastoid FD-NIRS & DCS outcomes against electromyography (EMG) and mouth pressure (Pm) during incremental inspiratory threshold loading (ITL). Six female and six male healthy adults (means ± SD; 30 ± 7 yr, maximum inspiratory pressure 118 ± 61 cmH2O) performed incremental ITL starting at low loads (8 ± 2 cmH2O) followed by 50-g increments every 2 min until task failure. FD-NIRS & DCS continuously measured sternocleidomastoid oxygenated and deoxygenated hemoglobin + myoglobin (oxy/deoxy[Hb + Mb]), tissue saturation of oxygen (StO2), BFi, and MRO2. Ventilatory parameters including inspiratory Pm were also evaluated. Pm increased during incremental ITL (P < 0.05), reaching −47[−74 to −34] cmH2O (median [IQR: 25%–75%]) at task failure. Ventilatory parameters were constant throughout ITL (all P > 0.05). Sternocleidomastoid BFi and MRO2 increased from the start of the ITL (both P < 0.05). Deoxy[Hb + Mb] increased close to task failure, concomitantly with a constant increase in MRO2, and decreased StO2. Sternocleidomastoid deoxy[Hb + Mb], BFi, StO2, and MRO2 obtained during ITL via FD-NIRS & DCS correlated with sternocleidomastoid EMG (all P < 0.05). In healthy adults, FD-NIRS & DCS can provide continuous surrogate measures of respiratory BFi and MRO2. Increasing sternocleidomastoid oxygen consumption near task failure was associated with increased oxygen extraction and reduced tissue saturation. NEW & NOTEWORTHY: This study introduces a novel approach, frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy (FD-NIRS & DCS), for noninvasive continuous monitoring of respiratory muscle blood flow and metabolic rate of oxygen consumption. Unlike prior methods involving invasive dye injection and magnetic resonance imaging, FD-NIRS & DCS offers the advantage of continuous measurement without the need for invasive procedures. It holds promise for advancing muscle physiology understanding and opens avenues for real-time monitoring of respiratory muscles. [ABSTRACT FROM AUTHOR]

The addition of absolute myocardial blood flow (MBF) data improves the diagnostic and prognostic accuracy of relative perfusion imaging with nuclear medicine. Cardiac-specific gamma cameras allow measurement of MBF with SPECT. This paper reviews the evidence supporting the use of SPECT to measure myocardial blood flow (MBF). Studies have evaluated SPECT MBF in large animal models and compared it in humans with invasive angiographic measurements and against the clinical standard of PET MBF. The repeatability of SPECT MBF has been determined in both single-site and multi-center trials. SPECT MBF has excellent correlation with microspheres in an animal model, with the number of stenoses and fractional flow reserve, and with PET-derived MBF. The inter-user coefficient of variability is ∼20% while the COV of test-retest MBF is ∼30%. SPECT MBF improves the sensitivity and specificity of the detection of multi-vessel disease over relative perfusion imaging and provides incremental value in predicting adverse cardiac events. SPECT MBF is a promising technique for providing clinically valuable information in the assessment of coronary artery disease. [ABSTRACT FROM AUTHOR]

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that causes vascular malformations throughout the body. The most prevalent and accessible of these lesions are found throughout the skin and mucosa, and often rupture causing bleeding and anemia. A recent increase in potential HHT treatments have created a demand for quantitative metrics that can objectively measure the efficacy of new and developing treatments. We employ optical coherence tomography (OCT)-a high resolution, non-invasive imaging modality in a novel pipeline to image and quantitatively characterize dermal HHT lesion behavior over time or throughout the course of treatment. This study is aimed at detecting detailed morphological changes of dermal HHT lesions to understand the underlying dynamic processes of the disease. We present refined metrics tailored for HHT, developed from a pilot study using 3 HHT patients and 6 lesions over the course of multiple imaging dates, totalling to 26 lesion images. Preliminary results from these lesions are presented in this paper alongside representative OCT images. This study provides a new objective method to analyse and understand HHT lesions using a minimally invasive, accessible, cost-effective, and efficient imaging modality with quantitative metrics describing morphology and blood flow.

ObjectiveCurrent guidelines for elective surgery of ascending thoracic aortic aneurysms (aTAAs) use aneurysm size as primary determinant for risk stratification of adverse events. Biomechanically, dissection may occur when wall stress exceeds wall strength. Determining patient-specific aTAA wall stresses by finite element analysis can potentially predict patient-specific risk of dissection. This study compared peak wall stresses in patients with ≥5.0 cm versus

BackgroundThe neonatal resuscitation program (NRP) recommends interrupted chest compressions (CCs) with ventilation in the severely bradycardic neonate. The conventional 3:1 compression-to-ventilation (C:V) resuscitation provides 90 CCs/min, significantly lower than the intrinsic newborn heart rate (120-160 beats/min). Continuous CC with asynchronous ventilation (CCCaV) may improve the success of return of spontaneous circulation (ROSC).MethodsTwenty-two near-term fetal lambs were randomized to interrupted 3:1 C:V (90 CCs + 30 breaths/min) or CCCaV (120 CCs + 30 breaths/min). Asphyxiation was induced by cord occlusion. After 5 min of asystole, resuscitation began following NRP guidelines. The first dose of epinephrine was given at 6 min. Invasive arterial blood pressure and left carotid blood flow were continuously measured. Serial arterial blood gases were collected.ResultsBaseline characteristics between groups were similar. Rate of and time to ROSC was similar between groups. CCCaV was associated with a higher PaO2 (partial oxygen tension) (22 ± 5.3 vs. 15 ± 3.5 mmHg, p

BACKGROUND: Single-center studies have shown that single photon emission computed tomography myocardial blood flow (MBF) measurement is accurate compared with MBF measured with microspheres in a porcine model, positron emission tomography, and angiography. Clinical implementation requires consistency across multiple sites. The study goal is to determine the intersite processing repeatability of single photon emission computed tomography MBF and the additional camera time required. METHODS: Five sites (Canada, Italy, Japan, Germany, and Singapore) each acquired 25 to 35 MBF studies at rest and with pharmacological stress using technetium-99m-tetrofosmin on a pinhole-collimated cadmium-zinc-telluride–based cardiac single photon emission computed tomography camera with standardized list-mode imaging and processing protocols. Patients had intermediate to high pretest probability of coronary artery disease. MBF was measured locally and at a core laboratory using commercially available software. The time a room was occupied for an MBF study was compared with that for a standard rest/stress myocardial perfusion study. With motion correction, the overall correlation in MBF between core laboratory and local site was 0.93 (range, 0.87–0.97) at rest, 0.90 (range, 0.84–0.96) at stress, and 0.84 (range, 0.70–0.92) for myocardial flow reserve. The local-to-core difference in global MBF (bias-MBF) was 5.4% (−3.8% to 14.8%; median [interquartile range]) at rest and 5.4% (−6.2% to 19.4%) at stress. Between the 5 sites, bias-MBF ranged from −1.6% to 11.0% at rest and from −1.9% to 16.3% at stress; the interquartile range in bias-MBF was between 9.3% (4.8%–14.0%) and 22.3% (−10.3% to 12.0%) at rest and between 17.0% (−11.3% to 5.6%) and 33.3% (−10.4% to 22.9%) at stress and was not significantly different between most sites. Both bias and interquartile range were like previously reported interobserver variability and less than the SD of the test-retest difference of 30%. The overall difference in myocardial flow reserve was 1.52% (−10.6% to 11.3%). There were no significant differences between with and without motion correction. The average additional acquisition time varied between sites from 44 to 79 minutes. CONCLUSIONS: The average bias-MBF and bias-MFR values were small with standard deviations substantially less than the test-retest variability. This demonstrates that MBF can be measured consistently across multiple sites and further supports that this technique can be reliably implemented. [ABSTRACT FROM AUTHOR]

Pattern separation, the ability to differentiate new information from previously experienced similar information, is highly sensitive to hippocampal structure and function and declines with age. Functional MRI studies have demonstrated hippocampal hyperactivation in older adults compared to young, with greater task-related activation associated with worse pattern separation performance. The current study was designed to determine whether pattern separation was sensitive to differences in task-free hippocampal cerebral blood flow (CBF) in 130 functionally intact older adults. Given prior evidence that apolipoprotein E e4 (APOE e4) status moderates the relationship between CBF and episodic memory, we predicted a stronger negative relationship between hippocampal CBF and pattern separation in APOE e4 carriers. An interaction between APOE group and right hippocampal CBF was present, such that greater right hippocampal CBF was related to better lure discrimination in noncarriers, whereas the effect reversed directionality in e4 carriers. These findings suggest that neurovascular changes in the medial temporal lobe may underlie memory deficits in cognitively normal older adults who are APOE e4 carriers.

PurposeThe mechanisms of brain metastasis are incompletely understood. Circulating tumor cells travel to the right heart and through the pulmonary circulation, where they may become lung metastases, and can circulate further to the left heart and brain. In patients who develop brain metastases without lung involvement, we hypothesized that cancer cells may travel directly from the right atrium to left atrium via a patent foramen ovale (PFO), akin to paradoxical embolism. If the prevalence of PFO is greater in these individuals compared to the general population (20-30%), PFO may play a role in brain metastasis, and prophylactic closure may provide benefit. Accordingly, we investigated the prevalence of PFO in patients with brain metastases without prior lung involvement.MethodsWe prospectively identified patients with brain metastases from a non-lung primary cancer with no preceding or concurrent lung involvement. Nine eligible participants underwent a transcranial Doppler study with intravenous agitated saline to assess for PFO.ResultsAmong nine participants, primary cancers were breast (n = 6), upper gastrointestinal (n = 2), and thyroid (n = 1). A positive bubble study was identified in 2/9 (22.2%) participants: one female with breast cancer and one male with duodenal adenocarcinoma. No participants developed lung metastases on subsequent chest imaging.ConclusionIn this prospective pilot study, we found a similar prevalence of PFO in patients who developed brain metastases without preceding lung involvement compared to estimates for the general population. Through a larger study is needed, the development of brain metastases in these individuals may primarily reflect tumor-specific biological factors diecting metastasis organotropism.

Background: The aim of this research was to determine the functional state of regional blood flow in young people with varying degrees of anatomical and functional disorders of periodontal tissues. Methods and Results: One hundred and thirty-five young patients with varying degrees of anatomical and functional disorders of periodontal tissues (AFDP) and 52 controls with intact periodontium were examined. All patients with AFDP were divided into three groups: Group 1 included 33 patients in the compensation stage (low degree of periodontal risk, intact periodontium, no clinical symptoms, pale pink gums, no bleeding on probing, dentogingival attachment is not disturbed); Group 2 included 38 patients in the sub-compensation stage (average degree of periodontal risk, disorders of the mucogingival complex, without clinical symptoms); and 64 patients in the decompensation stage (high degree of periodontal risk, disorders of the mucogingival complex, the presence of clinical symptoms, individual or combined signs of periodontal pathology, gingival recession (Class I and II according to Miller's classification). We studied the regional blood flow of periodontal tissues, which was assessed by an ultrasound Doppler graph in a non-invasive way. The parameters of linear (PSV, peak systolic velocity) and volumetric (Qs, maximum systolic volume velocity) velocities of blood flow, as well as the parameters of the wall vascularization (PI, pulsation index; RI, resistance index). Results: The PSV increased statistically significantly with a load compared to rest in the control and sub-compensation groups and decreased in the decompensation group with a load, compared to the rest condition. The PSV increased relative to the control in the subcompensation and decompensation groups in rest and under load. The Qs indicator showed a similar trend in the groups. Qs significantly increased under load, compared to the rest condition in the control, compensation, and subcompensation groups, and decreased in the decompensation group. The Qs values, in comparison with the control, increased in the subcompensation and decompensation groups in the rest condition and under load. The PI increased with the load relative to the rest condition in the control, compensation, and decompensation group. At the same time, PI decreased under the load, compared to the rest condition, in the subcompensation group. In comparison with the control, the PI values decreased in the subcompensation and decompensation groups in the rest condition and under load. The RI significantly changed only in the subcompensation group under load, compared to the rest condition. Only RI values decreased significantly in the subcompensation group under load, compared to the control. Conclusion: The use of Doppler ultrasonography in assessing the state of regional blood flow of periodontal tissues is a highly informative and non-invasive method. The velocity characteristics (linear and volumetric velocities) of blood flow are important diagnostic indicators, allowing the most rapid and reliable assessment of the degree of anatomical and functional disorders of periodontal tissues.

Hemorrhagic shock (HS) is a severe life-threatening condition characterized by loss of blood volume and a lack of oxygen (O2) delivery to tissues. The objective of this study was to examine the impact of manipulating Starling forces in the microcirculation during HS to increase microvascular perfusion without restoring blood volume or increasing O2 carrying capacity. To decrease interstitial tissue pressure, we developed a non-contact system to locally apply negative pressure and manipulate the pressure balance in capillaries, while allowing for visualization of the microcirculation. Golden Syrian hamsters were instrumented with dorsal window chambers and subjected to a controlled hemorrhaged of 50% of the animal's blood volume without any fluid resuscitation. A negative pressure chamber was attached to the dorsal window chamber and a constant negative pressure was applied. Hemodynamic parameters (including microvascular diameter, blood flow, and functional capillary density [FCD]) were measured before and during the four hours following the hemorrhage, with and without applied negative pressure. Blood flow significantly increased in arterioles during negative pressure. The increase in flow through arterioles also improved microvascular perfusion as reflected by increased FCD. These results indicate that negative pressure increases flow in the microcirculation when fluid resuscitation is not available, thus restoring blood flow, oxygen delivery, and preventing the accumulation of metabolic waste. Applying negative pressure might allow for control of microvascular blood flow and oxygen delivery to specific tissue areas.

PurposeTo develop geometric perfusion deficits (GPD), an optical coherence tomography angiography (OCTA) biomarker based on oxygen diffusion, and to evaluate its utility in a pilot study of healthy subjects and patients with diabetic retinopathy (DR).DesignRetrospective cross-sectional study.MethodsCommercial spectral-domain optical coherence tomography angiography (OCTA) instruments were used to acquire repeated 3 × 3-mm2 and 6 × 6-mm2 motion-corrected macular OCTA volumes. En face OCTA images corresponding to the superficial capillary plexus (SCP), deep capillary plexus (DCP), and full retinal projections were obtained using automatic segmentation. For each projection, the GPD percentage and the vessel density percentage, the control metric, were computed, and their values were compared between the normal and DR eyes. The repeated OCTA acquisitions were used to assess the test-retest repeatability of the GPD and vessel density percentages.ResultsRepeated OCTA scans of 15 normal eyes and 12 DR eyes were obtained. For all en face projections, GPD percentages were significantly higher in DR eyes than in normal eyes; vessel density percentages were significantly lower in all but 1 projection (DCP). Large GPD areas were used to identify focal perfusion deficits. Test-retest analysis showed that the GPD percentage had superior repeatability than the vessel density percentage in most cases. A strong negative correlation between the GPD percentage and the vessel density percentage was also found.ConclusionsGeometric perfusion deficits, an OCTA biomarker based on oxygen diffusion, provides a quantitative metric of macular microvascular remodeling with a strong physiological underpinning. The GPD percentage may serve as a useful biomarker for detecting and monitoring DR.

Advances in intravital microscopy (IVM) have enabled the studies of cellular organization and dynamics in the native microenvironment of intact organisms with minimal perturbation. The abilities to track specific cell populations and monitor their interactions have opened up new horizons for visualizing cell biology in vivo, yet the success of standard fluorescence cell labeling approaches for IVM comes with a "dark side" in that unlabeled cells are invisible, leaving labeled cells or structures to appear isolated in space, devoid of their surroundings and lacking proper biological context. Here we describe a novel method for "filling in the void" by harnessing the ubiquity of extracellular (interstitial) fluid and its ease of fluorescence labelling by commonly used vascular and lymphatic tracers. We show that during routine labeling of the vasculature and lymphatics for IVM, commonly used fluorescent tracers readily perfuse the interstitial spaces of the bone marrow (BM) and the lymph node (LN), outlining the unlabeled cells and forming negative contrast images that complement standard (positive) cell labeling approaches. The method is simple yet powerful, offering a comprehensive view of the cellular landscape such as cell density and spatial distribution, as well as dynamic processes such as cell motility and transmigration across the vascular endothelium. The extracellular localization of the dye and the interstitial flow provide favorable conditions for prolonged Intravital time lapse imaging with minimal toxicity and photobleaching.

The aim of this study was to assess the value of micro flow imaging (MFI) in distinguishing adenomatous polyps from cholesterol polyps. A total of 143 patients who underwent cholecystectomy for gallbladder polyps were retrospectively analyzed. B-mode ultrasound (BUS), color Doppler flow imaging (CDFI), MFI and contrast-enhanced ultrasound (CEUS) were performed before cholecystectomy. The weighted kappa consistency test was used to evaluate the agreement of vascular morphology among CDFI, MFI and CEUS. Ultrasound image characteristics, including BUS, CDFI and MFI images, were compared between adenomatous polyps and cholesterol polyps. The independent risk factors for adenomatous polyps were selected. The diagnostic performance of MFI combined with BUS in determining adenomatous polyps was compared with CDFI combined with BUS. Of the 143 patients, 113 cases were cholesterol polyps, and 30 cases were adenomatous polyps. The vascular morphology of gallbladder polyps was more clearly depicted by MFI than CDFI, and it had better agreement with CEUS. Differences in maximum size, height/width ratio, hyperechoic spot and vascular intensity on CDFI and MFI images were significant between adenomatous polyps and cholesterol polyps (p < 0.05). The maximum size, height/width ratio, and vascular intensity on MFI images were independent risk factors for adenomatous polyps. For MFI combined with BUS, sensitivity, specificity and accuracy were 90.00%, 94.69% and 93.70%, respectively. Area under the receiver operating characteristic curve (AUC) of MFI combined with BUS was significantly higher than that of CDFI combined with BUS (AUC = 0.923 vs. 0.784). Compared with CDFI combined with BUS, MFI combined with BUS had higher diagnostic performance in determining adenomatous polyps. [ABSTRACT FROM AUTHOR]

Endothelial cell (EC) metabolism is thought to be one of the driving forces for angiogenesis. Here we report the identification of the hexosamine D-mannosamine (ManN) as an EC mitogen and survival factor for bovine and human microvascular EC, with an additivity with VEGF. ManN inhibits glycosylation in ECs and induces significant changes in N-glycan and O-glycan profiles. We further demonstrate that ManN and two N-glycosylation inhibitors stimulate EC proliferation via both JNK activation and the unfolded protein response caused by ER stress. ManN results in enhanced angiogenesis in a mouse skin injury model. ManN also promotes angiogenesis in a mouse hindlimb ischemia model, with accelerated limb blood flow recovery compared to controls. In addition, intraocular injection of ManN induces retinal neovascularization. Therefore, activation of stress pathways following inhibition of protein glycosylation can promote EC proliferation and angiogenesis and may represent a therapeutic strategy for treatment of ischemic disorders.

The global burden of diabetes is rapidly increasing, from 451 million people in 2019 to 693 million by 20451. The insidious onset of type 2 diabetes delays diagnosis and increases morbidity2. Given the multifactorial vascular effects of diabetes, we hypothesized that smartphone-based photoplethysmography could provide a widely accessible digital biomarker for diabetes. Here we developed a deep neural network (DNN) to detect prevalent diabetes using smartphone-based photoplethysmography from an initial cohort of 53,870 individuals (the 'primary cohort'), which we then validated in a separate cohort of 7,806 individuals (the 'contemporary cohort') and a cohort of 181 prospectively enrolled individuals from three clinics (the 'clinic cohort'). The DNN achieved an area under the curve for prevalent diabetes of 0.766 in the primary cohort (95% confidence interval: 0.750-0.782; sensitivity 75%, specificity 65%) and 0.740 in the contemporary cohort (95% confidence interval: 0.723-0.758; sensitivity 81%, specificity 54%). When the output of the DNN, called the DNN score, was included in a regression analysis alongside age, gender, race/ethnicity and body mass index, the area under the curve was 0.830 and the DNN score remained independently predictive of diabetes. The performance of the DNN in the clinic cohort was similar to that in other validation datasets. There was a significant and positive association between the continuous DNN score and hemoglobin A1c (P ≤ 0.001) among those with hemoglobin A1c data. These findings demonstrate that smartphone-based photoplethysmography provides a readily attainable, non-invasive digital biomarker of prevalent diabetes.

RationaleCocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD).ObjectiveIn a phase II randomized clinical trial, to assess whether 6 months of cocoa improved walking performance in people with PAD, compared with placebo.Methods and resultsSix-month double-blind, randomized clinical trial in which participants with PAD were randomized to either cocoa beverage versus placebo beverage. The cocoa beverage contained 15 g of cocoa and 75 mg of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The 2 primary outcomes were 6-month change in 6-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A 1-sided P

Red blood cells (RBCs) transport oxygen to tissues and remove carbon dioxide. Diffuse optical flowmetry (DOF) assesses deep tissue RBC dynamics by measuring coherent fluctuations of multiply scattered near-infrared light intensity. While classical DOF measurements empirically correlate with blood flow, they remain far-removed from light scattering physics and difficult to interpret in layered media. To advance DOF measurements closer to the physics, here we introduce an interferometric technique, surmounting challenges of bulk motion to apply it in awake humans. We reveal two measurement dimensions: optical phase, and time-of-flight (TOF), the latter with 22 picosecond resolution. With this multidimensional data, we directly confirm the unordered, or Brownian, nature of optically probed RBC dynamics typically assumed in classical DOF. We illustrate how incorrect absorption assumptions, anisotropic RBC scattering, and layered tissues may confound classical DOF. By comparison, our direct method enables accurate and comprehensive assessment of blood flow dynamics in humans.

We aimed to investigate the roles of antegrade residual flow and leptomeningeal collateral flow in sustaining cerebral perfusion distal to an intracranial atherosclerotic stenosis (ICAS). Patients with apparently normal cerebral perfusion distal to a symptomatic middle cerebral artery (MCA)-M1 stenosis were enrolled. Computational fluid dynamics models were built based on CT angiography to obtain a translesional pressure ratio (PR) to gauge the residual antegrade flow. Leptomeningeal collaterals (LMCs) were scaled on CT angiography. Cerebral perfusion metrics were obtained in CT perfusion maps. Among 83 patients, linear regression analyses revealed that both translesional PR and LMC scale were independently associated with relative ipsilesional mean transit time (rMTT). Subgroup analyses showed that ipsilesional rMTT was significantly associated with translesional PR (p

BackgroundMicrovascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM).MethodsRandomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s-1) and low-shear (5 s-1) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM.ResultsWe randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p

The impact of the local inhibition of soluble epoxide hydrolase, which metabolizes vasodilator and anti-inflammatory epoxyeicosanoids, on diabetic skin microvascular dysfunction was assessed. In diabetic db/db mice, basal skin blood flow assessed using laser Doppler imaging was similar to that of control mice, but thermal hyperemia was markedly reduced. At 2 h after the topical administration of an aqueous gel containing the soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB: 400 mg/L), the peak concentration of t-AUCB was detected in the skin of diabetic mice, which quickly decreased thereafter. In parallel, 2 h after application of t-AUCB treatment, thermal hyperemia was increased compared to the control gel. Quantification of t-AUCB in plasma of treated animals showed no or low systemic diffusion. Furthermore, haematoxylin and eosin histological staining of skin biopsies showed that skin integrity was preserved in t-AUCB-treated mice. Finally, for pig ear skin, a surrogate for human skin, using Franz diffusion cells, we observed a continuous diffusion of t-AUCB from 2 h after application to beyond 24 h. A single topical administration of a soluble epoxide hydrolase inhibitor improves microcirculatory function in the skin of db/db mice and might represent a new therapeutic approach for preventing the development of skin complications in diabetic patients.

BackgroundHookah smoking is marketed to youth as a harmless alternative to cigarettes. Although cigarette smoking acutely impairs endothelial function, the effect of smoking fruit-flavored hookah tobacco is unknown. Because charcoal traditionally is used to heat the hookah tobacco in the waterpipe, hookah smoke delivers tobacco toxicants and nicotine plus charcoal combustion products: not only carbon-rich nanoparticles, oxidants that may destroy nitric oxide and impair endothelial function, but also large amounts of carbon monoxide (CO), a putative vasodilator molecule.MethodsTo test the acute effect of hookah smoking on endothelial function, in young adult hookah smokers (n=30, age 26±1 years, mean±SE), we measured plasma nicotine, exhaled CO, and brachial artery flow-mediated dilation (FMD) before and after charcoal-heated hookah smoking. To remove the effect of charcoal combustion, the same measurements were performed when the same flavored hookah tobacco product was heated electrically (n=20). As a positive internal control, we studied age-matched cigarette smokers (n=15) who smoked 1 cigarette. To isolate the effect of the CO boost on FMD, hookah smokers (n=8) inhaled a 0.1% CO gas mixture to approximate their CO boost achieved with charcoal-heated hookah smoking.ResultsNicotine levels increased similarly with all types of smoking, whereas exhaled CO increased 9- to 10-fold more after charcoal-heated hookah than after either electrically heated hookah or cigarette smoking. FMD did not decrease after smoking charcoal-heated hookah but instead increased by +43±7% ( P

Since of its introduction in 1980s, laser speckle imaging has become a powerful tool in flow imaging. Its high performance and low cost made it one of the preferable imaging methods. Initially, speckle contrast measurements were the main algorithm for analyzing laser speckle images in biological flows. Speckle contrast measurements, also referred as Laser Speckle Contrast Imaging (LSCI), use statistical properties of speckle patterns to create mapped image of the blood vessels. In this communication, a new method named Laser Speckle Optical Flow Imaging (LSOFI) is introduced. This method uses the optical flow algorithms to calculate the apparent motion of laser speckle patterns. The differences in the apparent motion of speckle patterns are used to identify the blood vessels from surrounding tissue. LSOFI has better spatial and temporal resolution compared to LSCI. This higher spatial resolution enables LSOFI to be used for autonomous blood vessels detection. Furthermore, Graphics Processing Unit (GPU) based LSOFI can be used for quasi real time imaging.

Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel β subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation. This resulted in ventricular arrhythmias in all mice (15/15) and SCD in 5/15 mice during reperfusion. Strikingly, prior RIPC (limb or liver) greatly reduced the incidence and severity of all ventricular arrhythmias and completely prevented SCD. Biochemical and pharmacological analysis demonstrated that RIPC cardioprotection required ERK1/2 and/or AKT phosphorylation. A lack of alteration in GSK-3β phosphorylation suggested against conventional reperfusion injury salvage kinase (RISK) signaling pathway protection. If replicated in human studies, limb RIPC could represent a noninvasive, nonpharmacological approach to limit dangerous ventricular arrhythmias associated with ischemia and/or channelopathy-linked SCD.

BACKGROUND:High ultrafiltration rate (UFR) has been associated with increased mortality in hemodialysis (HD) patients. However, the impact of UFR on decline of residual kidney function (RKF) has not been elucidated among patients receiving conventional HD. METHODS:We performed a retrospective cohort study of 7,753 patients who initiated conventional HD from 2007 to 2011 and survived the first year of dialysis with baseline UFR and renal urea clearance (KRU) data at baseline and 1 year (5th patient-quarter). The primary exposure was average UFR at the 1st patient-quarter from dialysis initiation (

The Fontan procedure provides relief from cyanosis in patients with univentricular hearts. A major clinical unmet need is to understand whether the venous flow patterns of the Fontan circulation lead to the development of congestive hepatopathy and other life-threatening complications. Currently, there is no consensus on whether heart beat or respiration is the main driving force of venous return and which one affects the periodic flow changes for the most (i. e., pulsatility). The present study, for the first time, quantified respiratory and cardiac components of the venous flow in the inferior vena cava (IVC) of 14 Fontan patients and 11 normal controls using a novel approach ("physio-matrix"). We found that in contrast to the normal controls, respiration in Fontan patients had a significant effect on venous flow pulsatility, and the ratio of respiration-dependent to the cardiac-dependent pulsatility was positively associated with the retrograde flow. Nevertheless, the main driving force of net IVC flow was the heart beat and not respiration. The separate analysis of the effects of respiration and heart beat provides new insights into the abnormal venous return patterns that may be responsible for adverse effects on liver and bowel of the patients with Fontan circulation.

The purpose of this study was to investigate lower limb blood flow responses under varying blood flow restriction (BFR) pressures based on individualized limb occlusion pressures (LOP) using a commonly used occlusion device. Twenty-nine participants (65.5% female, 23.8 ± 4.7 years) volunteered for this study. An 11.5cm tourniquet was placed around participants' right proximal thigh, followed by an automated LOP measurement (207.1 ± 29.4mmHg). Doppler ultrasound was used to assess posterior tibial artery blood flow at rest, followed by 10% increments of LOP (10-90% LOP) in a randomized order. All data were collected during a single 90-minute laboratory visit. Friedman's and one-way repeated-measures ANOVAs were used to examine potential differences in vessel diameter, volumetric blood flow (VolFlow), and reduction in VolFlow relative to rest (%Rel) between relative pressures. No differences in vessel diameter were observed between rest and all relative pressures (all p < .05). Significant reductions from rest in VolFlow and %Rel were first observed at 50% LOP and 40% LOP, respectively. VolFlow at 80% LOP, a commonly used occlusion pressure in the legs, was not significantly different from 60% (p = .88), 70% (p = .20), or 90% (p = 1.00) LOP. Findings indicate a minimal threshold pressure of 50%LOP may be required to elicit a significant decrease in arterial blood flow at rest when utilizing the 11.5cm Delfi PTSII tourniquet system. [ABSTRACT FROM AUTHOR]

Dermascopes are commonly utilized for the qualitative visual inspection of skin lesions. While automated image processing techniques and varied illumination strategies have been used to aid in structural analysis of lesions, robust quantification of functional information is largely unknown. To address this knowledge gap, we have developed a compact, handheld dermascope that enables real-time blood flow measurements of skin during conventional visual inspection. In-vitro characterization demonstrated that the dermascope is capable of quantifying changes in flow across a physiologically relevant range even when used in a handheld manner with clinic lighting and dermascope LEDs on. In a small pilot clinical study, we demonstrated the dermascope's ability to detect flow differences between two distinct lesion types.

ObjectivesAdequate assessment of fluid responsiveness in shock necessitates correct interpretation of hemodynamic changes induced by preload challenge. This study evaluates the accuracy of point-of-care Doppler ultrasound assessment of the change in carotid corrected flow time induced by a passive leg raise maneuver as a predictor of fluid responsiveness. Noninvasive cardiac output monitoring (NICOM, Cheetah Medical, Newton Center, MA) system based on a bioreactance method was used.DesignProspective, noninterventional study.SettingICU at a large academic center.PatientsPatients with new, undifferentiated shock, and vasopressor requirements despite fluid resuscitation were included. Patients with significant cardiac disease and conditions that precluded adequate passive leg raising were excluded.InterventionsCarotid corrected flow time was measured via ultrasound before and after a passive leg raise maneuver. Predicted fluid responsiveness was defined as greater than 10% increase in stroke volume on noninvasive cardiac output monitoring following passive leg raise. Images and measurements were reanalyzed by a second, blinded physician. The accuracy of change in carotid corrected flow time to predict fluid responsiveness was evaluated using receiver operating characteristic analysis.Measurements and main resultsSeventy-seven subjects were enrolled with 54 (70.1%) classified as fluid responders by noninvasive cardiac output monitoring. The average change in carotid corrected flow time after passive leg raise for fluid responders was 14.1 ± 18.7 ms versus -4.0 ± 8 ms for nonresponders (p < 0.001). Receiver operating characteristic analysis demonstrated that change in carotid corrected flow time is an accurate predictor of fluid responsiveness status (area under the curve, 0.88; 95% CI, 0.80-0.96) and a 7 ms increase in carotid corrected flow time post passive leg raise was shown to have a 97% positive predictive value and 82% accuracy in detecting fluid responsiveness using noninvasive cardiac output monitoring as a reference standard. Mechanical ventilation, respiratory rate, and high positive end-expiratory pressure had no significant impact on test performance. Post hoc blinded evaluation of bedside acquired measurements demonstrated agreement between evaluators.ConclusionsChange in carotid corrected flow time can predict fluid responsiveness status after a passive leg raise maneuver. Using point-of-care ultrasound to assess change in carotid corrected flow time is an acceptable and reproducible method for noninvasive identification of fluid responsiveness in critically ill patients with undifferentiated shock.

PROBLEM:Premature birth complicates 10%-12% of deliveries. Infection and inflammation are the most common etiologies and are associated with increased offspring morbidity and mortality. We hypothesize that lipopolysaccharide (LPS)-induced maternal inflammation causes direct placenta injury and subsequent injury to the fetal intestine. METHOD OF STUDY:Pregnant C57Bl6 mice were injected intraperitoneally on day 15.5 with 100 μg/kg LPS or saline. Maternal serum, amniotic fluid, placental samples, and ileal samples of offspring were obtained assessed for inflammation and/or injury. Maternal placental ultrasounds were performed. Placental DNA was isolated for microbiome analysis. RESULTS:Maternal injection with LPS caused elevated IL-1β, IL-10, IL-6, KC-GRO, and TNF. Placental tissue showed increased IL-1β, IL-6, and KC-GRO and decreased IL-10, but no changes were observed in amniotic fluid. Placental histology demonstrated LPS-induced increases in mineralization and necrosis, but no difference in placental blood flow. Most placentas had no detectable microbiome. Exposure to maternal LPS induced significant injury to the ilea of the offspring. CONCLUSION:Lipopolysaccharide causes a maternal inflammatory response that is mirrored in the placenta. Placental histology demonstrates structural changes; however, placental blood flow is preserved. LPS also induces an indirect intestinal injury in the offspring that lasts beyond the neonatal period.

Vasovagal syncope (VVS) is characterized by hypotension and bradycardia followed by lowering of cerebral blood flow. Remote limb ischemic preconditioning (RIPC) is well documented to provide cardio- and neuroprotection as well as to improve cerebral blood flow. We hypothesized that RIPC will provide protection against VVS-induced hypotension, bradycardia, and cerebral hypoperfusion. Second, because endothelial nitric oxide synthase has been reported as a mediator of cerebral blood flow control, we hypothesized that the mechanism by which RIPC primes the vasculature against VVS is via the α1-adrenoceptor-protein kinase Cε-endothelial nitric oxide synthase pathway. We utilized sinusoidal galvanic vestibular stimulation in rats as a model of VVS. RIPC attenuated the lowerings of mean arterial pressure, heart rate, and cerebral blood flow caused by sinusoidal galvanic vestibular stimulation, as well as improving behavior during, and recovery after, stimulation. RIPC induced elevated serum norepinephrine, increased expression of brain α1-adrenoceptors, and reduced brain expression of norepinephrine transporter 1. Antagonizing adrenoceptors and norepinephrine transporter 1 prevented RIPC protection of cerebral perfusion during sinusoidal galvanic vestibular stimulation. Taken together, this study indicates that RIPC may be a potential therapy that can prevent VVS pathophysiology, decrease syncopal episodes, and reduce the injuries associated with syncopal falls. Furthermore, the α1-adrenoceptor-protein kinase Cε-endothelial nitric oxide synthase pathway may be a therapeutic target for regulating changes in cerebral blood flow.

AimsHemodynamic shear stress participates in maintaining vascular redox status. Elucidating flow-mediated endothelial metabolites enables us to discover metabolic biomarkers and therapeutic targets. We posited that flow-responsive vascular endothelial growth factor receptor (VEGFR)-protein kinase C isoform epsilon (PKCɛ)-6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling modulates glycolytic metabolites for vascular repair.ResultsBidirectional oscillatory flow (oscillatory shear stress [OSS]: 0.1 ± 3 dyne·cm-2 at 1 Hz) upregulated VEGFR-dependent PKCɛ expression to a greater degree than did unidirectional pulsatile flow (pulsatile shear stress [PSS]: 23 ± 8 dyne·cm-2 at 1 Hz) in human aortic endothelial cells (p

Background: Peripheral arterial disease affects >200 million people worldwide and is characterized by impaired blood flow to the lower extremities. There are no effective medical treatments available. Using the mouse hind-limb ischemia model and miRNA sequencing, we identified a novel miRNA, miR-6236, whose expression significantly elevated in ischemic mouse limbs compared with nonischemic limbs. The role of miR-6236 in general or in postischemic angiogenesis is not known. Here we describe its role using in vivo and in vitro models of peripheral arterial disease., Methods and Results: In primary mouse and human endothelial cells, we studied the effect of simulated ischemia on miR-6236 expression and assessed its role in cell viability, apoptosis, migration, and tube formation during ischemia. Furthermore, we developed miR-6236 null mice and tested its role in postischemic perfusion recovery using the hind-limb ischemia model. Lastly, using bioinformatics and gene expression analysis, we identified putative angiogenic miR-6236 targets. In vitro simulated ischemia-enhanced miR-6236 expression in mouse and human endothelial cells, whereas its inhibition improved viability, migration, tube formation, and reduced apoptosis. In vivo ischemic mouse skeletal muscle tissue showed higher miR-6236 expression compared with nonischemic muscles. Loss of miR-6236 improved impaired postischemic perfusion recovery and poor angiogenesis associated with streptozotocin-induced diabetes in mice. Six of the 8 miR-6236 predicted angiogenic target mRNAs showed expression consistent with regulation by miR-6236 in ischemic skeletal muscle., Conclusions: Our results show for the first time that miR-6236 plays a key role in regulating postischemic perfusion recovery and angiogenesis.

Background: Adipsin (complement factor D, CFD), as the first described adipokine, is well-known for its regulatory effects in diabetic cardiovascular complications. However, its role in diabetic hind-limb ischemia was not clarified. This study aimed to evaluate the possible therapeutic effect of Adipsin in hind-limb ischemia in type 2 diabetic mice and to elucidate the molecular mechanisms involved., Methods: A high-fat diet and streptozotocin (HFD/STZ)-induced diabetic mouse model, and a transgenic mouse model with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg) were employed. Hindlimb ischemia was established by femoral artery ligation, and blood flow recovery was monitored using Laser Doppler perfusion imaging. Molecular mechanisms underlying Adipsin-potentiated angiogenesis were examined using RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses., Results: Adipsin expression was upregulated in non-diabetic mice following HLI, while suppressed in diabetic mice, indicating its potential role in ischemic recovery which is impaired in diabetes. Adipsin-Tg mice exhibited significantly improved blood flow recovery, increased capillary density, and enhanced muscle regeneration in comparison with non-transgenic (NTg) diabetic mice. Adipsin facilitated proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) under hyperglycemic and hypoxic conditions. Additionally, it enhanced phosphorylation of AKT, ERK, and eNOS pathways both in vivo and in vitro. RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses identified that Adipsin promoted angiogenesis by interacting with SERBP1, which disrupted the binding of SERBP1 to SERPINE1 mRNA, resulting in reduced SERPINE1 expression and the subsequent activation of the VEGFR2 signaling cascade., Conclusions: Adipsin promotes angiogenesis and facilitates blood perfusion recovery in diabetic mice with HLI by downregulating SERPINE1 through interaction with SERBP1. These findings elucidate a novel therapeutic potential for Adipsin in the management of PAD in diabetic patients, highlighting its role in enhancing angiogenesis and tissue repair., Competing Interests: Declarations. Ethics approval and consent to participate: All experimental animal procedures were approved by the Animal Care and Use Committee of the Air Force Medical University and followed the Animal Research Advisory Committee of the National Institutes of Health guidelines (Approval ID: 20201017). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The accuracy of femoral artery blood flow measurements via Doppler ultrasound hinges on assumptions of laminar flow upstream of the femoral bifurcation. Existing scanning guidelines recommend a minimum proximity to the flow divider of 2-3 cm for avoiding multidirectional blood flow yet lack experimental evidence to support this recommendation. This study aimed to determine the minimum distance required to avoid multidirectional flow contamination near the femoral bifurcation and to assess the reliability of vector flow imaging (VFI) in these measurements. Twenty healthy adults (10 females, 25 ± 4 yr) participated in this study. Ultrasound VFI was used to visualize blood flow patterns and quantify flow uniformity via vector concentration coefficient (VCC), and multidirectional flow length was quantified at rest in triplicate ( n = 20), postisometric contraction ( n = 20), and during thigh cuffing ( n = 10). At rest, the mean multidirectional flow length was 3.12 ± 0.59 cm, which decreased to 2.80 ± 0.66 cm postcontraction ( P = 0.02). Thigh cuffing (80 mmHg) resulted in a multidirectional flow length of 2.75 ± 0.64 cm, not significantly different from rest ( P = 0.69). Males exhibited a shorter multidirectional flow length compared with females (mean difference: 0.31 ± 0.71 cm, P = 0.05). The VCC increased from 0.39 ± 0.08 at rest to 0.57 ± 0.15 postcontraction ( P < 0.01), indicating increased flow uniformity. Reliability metrics demonstrated good-to-excellent reproducibility at rest, with intraclass correlation coefficient [ICC(3,1)] = 0.85 and 0.84 and coefficient of variation (CV)% = 7.1 ± 6.2% and 7.5 ± 4.5% for multidirectional flow length and VCC, respectively. Our data suggest a minimum scanning proximity of 3.5 cm to the femoral bifurcation to ensure that blood flow assessments are free of multidirectional flow and invite further study in different body positions and arteries of interest to increase rigor in this area. NEW & NOTEWORTHY Current ultrasound scanning guidelines to avoid multidirectional flow contamination in the femoral artery of 2-3 cm lack supporting evidence. We used vector flow imaging to report the multidirectional flow length during rest and manipulation of downstream vessel resistance in males and females. We suggest measurements at least 3.5 cm upstream from the femoral bifurcation to minimize multidirectional flows. This study also supports reliability of vector flow imaging for femoral artery assessments, with good-to-excellent reproducibility of results.

Background: Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development., Methods: We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral responses to blood flow. Additionally, genetic mutants and pharmacological modulators were used in zebrafish in vivo to study the impacts of CXCR3 loss and gain of function on vascular development., Results: In vitro modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with ECs and expansion of the vasculature in zebrafish treated with the Cxcr3 inhibitor AMG487 or in homozygous cxcr3.1/3.2/3.3 triple mutants. We also demonstrate that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared with their control counterparts., Conclusions: Our results suggest that CXCR3 signaling in ECs helps promote vascular stabilization events during development by preventing EC overgrowth and promoting pericyte recruitment., Competing Interests: None.

Background: A mature arteriovenous fistula (AVF) is the preferred hemodialysis access owing to its durability and lower risk of complications. Various factors have been implicated as predictors for maturation, including vein diameter and access type. Vein distensibility, which refers to the ability of the vein to dilate in response to changes in blood flow and pressure, has been proposed as a potential predictor for maturation, but its utility remains poorly studied., Methods: This is a single-institution retrospective study of AVFs performed under regional anesthesia. Vein distensibility was defined as the absolute and relative difference in target vein diameter (TVD) between the preoperative ultrasound vein mapping performed with tourniquet and a repeat ultrasound examination after a regional block before AVF creation and without a tourniquet., Results: Forty-six patients underwent first-time AVF surgery with distensibility recorded in a prospectively maintained database. The mean initial preoperative TVD was 2.7 mm, and after the block 3.4 mm. The unassisted maturation rate for the entire cohort was 76%. In patients with an absolute change of TVD of <0.5 mm (Δ<0.5), the unassisted maturation rate was 63% (12/19), even though 95% of the group had a preoperative TVD of >3 mm. In those with ≥0.5 mm, the unassisted maturation rate was 85% (23/27; P = .08), even though the preoperative vein map TVD was 2.3 mm and 75% had a vein map TVD of <3 mm. For radiocephalic AVFs (n = 26), the unassisted maturation rate was 75% for Δ<0.5 vs 94% for Δ≥0.5 (P = .16), despite a preoperative vein map TVD of >3 mm in 92% vs 75%, respectively. The receiver operatring characteristic area under the curve for unassisted maturation with a Δ≥0.5 mm was 0.68 (P = .26)., Conclusions: Quality in dialysis access surgery requires optimizing the unassisted maturation rate. A physiological measure that accounts for the dynamic process of maturation may be more informative than anatomic measurements alone. The results shown here demonstrate that vein distensibility may be a better predictor than absolute vein diameter on standard vein mapping ultrasound examinations., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Promoting the establishment of collateral circulation is essential for chronic lower extremity ischemia. However, no effective therapeutic drugs have yet been developed. Recent studies discovered that in the peripheral arteries, there are γ-aminobutyric acid B1 (GABAB1) receptors expressed in endothelial cells and smooth muscle cells, these receptors may have some effects in regulating vascular functions, but the precise mechanism is not yet clear. This study explores the effect of GABAB1 receptor inhibition on angiogenesis and its regulatory mechanism. The expression of GABAB1 in human umbilical vein endothelial cells (HUVECs) was knocked down using shRNA transfection, and effects on HUVECs' proliferation, migration, and tube formation ability were detected. Western blot and RT-PCR were used to verify the signal pathway. The murine hind limb ischemia model was used to verify the effect of CGP35348, an antagonist of GABAB1R, on the recovery of blood flow perfusion and angiogenesis in ischemic tissues. Cell proliferation, migration, and tube formation ability were improved after GABAB1 receptor knockdown in HUVECs. The phosphorylation of the HIPPO/Yes-associated protein (YAP) pathway decreased, while the effect of promoting angiogenesis increased. After treating the ischemic hindlimbs of mice with GABAB1 receptor antagonists, the blood flow perfusion recovered and the angiogenesis increased. These findings demonstrate the effect of GABAB1 receptor inhibition on the HIPPO/YAP pathway in regulating angiogenesis, suggesting that inhibiting GABAB1 receptor levels might be a novel approach for chronic lower extremity ischemia diseases., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: To study outcomes in patients with non-thrombotic iliac vein lesions (NIVLs) treated by stents., Methods: We performed a retrospective study that collected 109 patients from January 2016 to August 2020 diagnosed with symptomatic NIVLs. The patients underwent endovenous stenting using the Wallstents. Clinical severity was assessed using the venous clinical severity score and the Villalta scores. The patency was assessed using duplex ultrasound, while the diameters and the blood flow velocities (BFVs) in the proximal, middle, and distal stented segments were recorded simultaneously., Results: A total of 128 stents were placed in 115 limbs (median age, 61 years), with a mean follow-up of 32 months. At 36 months, the Villalta scores went from 12.17 to 3.64 ( p < .001). The VCSS went from 9.41 to 3.31 ( p < .001). The mean diameters in the proximal, middle, and distal stented segments were 8.52 ± 2.15 mm, 10.13 ± 1.75 mm, and 10.17 ± 1.69 mm in the first month, while the mean BFVs were 31.17 ± 13.66 cm/s, 31.07 ± 11.90 cm/s, and 36.39 ± 18.41 cm/s, respectively. Repeated-measures analysis in 55 consecutive patients from 1 month to 3 years after procedure revealed a decrease of the stent diameter in the proximal stented segment ( p = .004); a stabilization of the stent diameter in the middle ( p = .43) or distal ( p = .45) stented segment; a steadiness of the BFVs in the proximal ( p = .40), middle ( p = .93), and distal ( p = .25) stented segments; and an improvement in the VCSS ( p = .03) and Villalta scores ( p = .006)., Conclusions: BFVs in stented segments remained steady and the symptoms in lower extremities improved after surgery, while stent compression was observed in the diameter of the proximal stented segment, with no impact on BFVs or symptoms., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Anticoagulation and antiplatelet therapy effectively inhibit neointimal hyperplasia (NIH) in both arterial and venous systems but not in arteriovenous fistulae (AVF). The main site of AVF failure is the juxta-anastomotic area that is characterized by disturbed flow compared with laminar flow in the arterial inflow and the venous outflow., Objectives: We hypothesized that early thrombus formation is required for eccentric and heterogeneous NIH in the presence of disturbed flow., Methods: Needle puncture and sutured AVF were created in C57BL/6 mice, in PF4-Cre × mT/mG reporter mice, and in Wistar rats. Human AVF samples were second-stage basilic vein transpositions. The tissues were examined by histology, immunofluorescence, immunohistochemistry, and en face staining., Results: In the presence of disturbed flow, both mouse and human AVF showed eccentric and heterogeneous NIH. Maladapted vein wall was characterized by eccentric and heterogeneous neointima that was composed of a different abundance of thrombus and smooth muscle cells. PF4-cre × mT/mG reporter mice AVF showed that green fluorescent protein-labeled platelets deposit on the wall directly facing the fistula exit with endothelial cell loss and continue to accumulate in the presence of disturbed flow. Neither disturbed flow with limited endothelial cell loss nor nondisturbed flow induced heterogeneous neointima in different animal models., Conclusion: Early thrombus contributes to late heterogeneous NIH in the presence of disturbed flow. Disturbed flow, large area of endothelial cell loss, and thrombus formation are critical to form eccentric and heterogeneous NIH. Categorization of adapted or maladapted walls may be helpful for therapy targeting heterogeneous NIH., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Published by Elsevier Inc.)

Background: Micronized purified flavonoid fraction (MPFF) is the most widely prescribed and well-studied venoactive drug available for the treatment of chronic venous disease (CVD). Photoplethysmography (PPG) is used to quantitatively measure venous hemodynamics and provide information about the overall function of the venous system. The aim of this study was to use digital PPG to evaluate the effects of MPFF on venous hemodynamics in patients with CVD., Methods: Patients diagnosed with CVD at an outpatient clinic in Bursa, Turkey between February 2018 and July 2020 were assessed for inclusion in this retrospective analysis. Patients who complied with the advised treatment strategy (MPFF 1,000 mg tablets taken orally once daily and compression garments) and attended follow-up visits were included in the analysis. Digital PPG was used to measure venous refilling time (VRT) and venous pumping capacity (VPC) at diagnosis and 6 months of follow-up. The Venous Clinical Severity Score (VCSS) was also obtained at these visits, and patients completed the 20-item Chronic Venous Insufficiency Questionnaire (CIVIQ-20)., Results: In total, 721 patients (mean age 52 years) with C0-C4 CVD were included in the study. PPG showed that VRT and VPC increased significantly from 19.0 sec to 2.0%, respectively, at diagnosis to 27.4 and 4.9%, respectively, at 6 months (both P < 0.05). Mean VCSS improved significantly from 7.9 at diagnosis to 3.1 at 6 months (P < 0.05). Mean CIVIQ-20 score also improved significantly at the 6-month follow-up (20.1 vs 38.6 at diagnosis; P < 0.01)., Conclusions: In patients with C0-C4 CVD, 6 months of MPFF treatment plus the wearing of compression garments was associated with statistically significant improvements in venous hemodynamic parameters measured by PPG, as well as measures of clinical severity and quality of life., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: In the treatment of chronic limb-threatening ischemia (CLTI), complete wound healing is an important goal. Although foot perfusion status seems to be important for wound healing, the Global Limb Anatomic Staging System (GLASS) of the Global Vascular Guidelines does not include pedal artery status for the staging process due to the lack of sufficient evidence of its importance. This study aimed to clarify the importance of pedal perfusion status after bypass surgery., Methods: Among the 153 CLTI cases that underwent bypass distal to popliteal arteries from 2014 to 2018, 117 CLTI limbs with wounds and with sufficient pedal angiographic data were enrolled. They were classified into two groups, based on the wound status 6 months postoperatively; early wound healing group (EWG; n = 78), which achieved complete wound healing within 6 months postoperatively, and prolonged healing or unhealed wounds group (PWG; n = 39), which failed to achieve wound healing within 6 months. Various factors associated with wound healing, including the wound, ischemia, and foot infection (WIfI) classification, intraoperative graft flow, and pedal angiographic data, were analyzed. Regarding pedal angiographic data, in addition to the GLASS inframalleolar/pedal disease descriptor (IPD), newly formed classification system of the pedal circulation status in association with the location of wounds was included: pedal circulation status was classified into two groups as visualized arterial perfusion towards wounds (visualized perfusion) and non-visualized arterial perfusion towards wounds (non-visualized perfusion)., Results: Univariate analysis showed preoperative albumin (Odds ratio [OR], 0.47; 95% confidence interval [CI], 0.24-0.94; P = .027), higher WIfI clinical stage (OR, 3.88; 95% CI, 1.74-10.1; P = .0005), higher IPD (OR, 2.16; 95% CI, 1.16-4.02; P = .012), and non-visualized perfusion to wounds (OR, 5.74: 95% CI, 2.45-14.0; P < .0001) as significant for prolonged wound healing. Multivariate analysis showed higher WIfI stage (OR, 5.04; 95% CI, 1.74-14.6; P = .0029) and non-visualized perfusion to wounds (OR, 4.34; 95% CI, 1.71-11.0; P = .0021) as significant, whereas IPD was not detected as significant. Regarding blood supply to the foot, although graft flow was significantly lower in IPD-P2 than IPD-P0/P1, graft flow was similar regardless of the status of angiographic circulation to wounds, suggesting that distribution of blood supply to the wound would be more important than total amount of blood supply to the foot for wound healing., Conclusions: WIfI clinical stage and pedal circulatory environment were important factors for wound healing after bypass surgery. Pedal anatomical classification system including perfusion status would be important for decision making in CLTI treatment., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Duplex ultrasound (DUS)-measured peak systolic velocity ratios (PSVRs) are commonly used to evaluate arterial stenosis in lower extremity artery disease (LEAD). However, these measurement methods have not yet been standardized. This study aimed to reveal the influence of measuring methods on PSVR values., Methods: A 132 femoropopliteal lesions with PSVR ranging from 1.5 to 3.5 evaluated using method A (angle correction 60°, the direction of blood flow, the no or few atherosclerotic changes closest to the lesion proximal side was defined as the nonstenotic area) were included. The following 4 different methods were then compared with method A: method B, angle correction 45°; method C, angle correction 60° measured along the vessel wall; D, angle correction 60°, with the nonstenotic area the lowest peak systolic velocity area; and E, angle correction 60°, with the reference point fixed at 2 cm proximal to the target lesion area. The difference in PSVR values was analyzed using the Bland-Altman method., Results: The mean PSVR value measured by method A was 2.27±0.51, those measured by methods B, C, D, and E were 2.21±0.55, 2.31±0.66, 2.34±0.63, and 2.11±0.63, respectively. The 95% prediction intervals of the differences in PSVR measurements versus A were -0.64 to +0.53 for method B, -0.59 to +0.68 for method C, -0.77 to +0.91 for method D, and -1.12 to +0.79 for method E., Conclusion: PSVR values considerably differed between measuring methods. PSVR values by DUS are largely dependent on the measurement methods, which could considerably affect the judgment of LEAD., Clinical Impact: Due to differences in several DUS measurement methods, the PSVR results could be changed. Therefore, to need further investigations and unification of measurement method., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Diagnosis of chronic upper limb ischemia is mainly clinical. Although hand perfusion can be evaluated by different noninvasive methods (e.g., digital-brachial index, digital pressures, oxygen saturation measurements, and plethysmography), these have not been standardized for the diagnosis of chronic upper limb ischemia. Initial reports suggested that the hand acceleration time (HAT) measured by duplex ultrasound could be a useful diagnostic tool. However, the HAT has neither been properly characterized nor validated. This study aimed to provide evidence that HAT is a sensitive diagnostic tool for chronic upper limb ischemia., Methods: We conducted a prospective, single-center, cross-sectional study with adult patients diagnosed with chronic upper limb ischemia and healthy adult volunteers without cardiovascular risk factors. Hand vascular duplex ultrasound and HAT measurement were performed in 4 artery locations: princeps pollicis artery, radialis indicis artery, first common digital palmar artery, and third common digital palmar artery. It was also measured in the ulnar and radial arteries. Descriptive and exploratory analyses were performed between patients and healthy volunteers., Results: Thirty participants were included, being 15 patients (median [standard deviation] age: 51 [18] years; 47% women) and 15 healthy volunteers (median [standard deviation] age: 35 [10] years; 60% women). In total, 15 ischemic and 30 nonischemic hands were analyzed. Humeral artery stenosis/occlusion (n = 6, 40.0%) and distal artery stenosis (n = 5, 33.3%) were the main causes of ischemia. Median (interquartile range) HAT measurements were significantly different between patients and healthy volunteers in the 4 hand arterial locations, the radial artery, and ulnar artery: princeps pollicis artery: 164 (124-252) vs. 60 (40-88), P < 0.001; radialis indicis artery: 176 (140-348) vs. 60 (36-80), P < 0.001; first common digital palmar artery: 180 (92-320) vs. 64 (36-88), P < 0.001; third common digital palmar artery: 180 (104-240) vs. 56 (44-92), P < 0.001; radial artery: 156 (120-248) vs. 68 (55-76), P < 0.001; and ulnar artery: 152 (76-220) vs. 61 (48-76), P < 0.001., Conclusions: Vascular duplex ultrasound with HAT measurement seems to be an easy-access, sensitive diagnostic tool for chronic upper limb ischemia. HAT provides valuable information on hand perfusion and may be complementary to current noninvasive methods., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Microvascular ultrasound imaging techniques such as Angio PLanewave UltraSensitive (Angio-PL.U.S.) have been used to detect microvascular blood flow in various organs and tissues. However, the advantage of Angio-PL.U.S. for assessing muscle microvascularity over other non-invasive imaging modalities has not been investigated. This cross-sectional study compared ultrafast Angio-PL.U.S. and conventional color Doppler flow imaging (CDFI) techniques for assessing intramuscular blood perfusion., Methods: Forty-five older adults participated (age = 59.1 ± 7.6). The vascularity index (VI) was used to quantify intramuscular blood flow of the bilateral biceps brachii (BB) and medial gastrocnemius (MG). Intra-limb (difference in VI between CDFI and Angio-PL.U.S. techniques) and inter-limb differences [percent side-to-side differences (%SSD) in VI between dominant and non-dominant sides] were compared using Wilcoxon Signed Ranks and Mann-Whitney U tests, respectively. Associations between techniques were assessed using Spearman's rho (ρ)., Results: No significant differences were observed between dominant and non-dominant BB (p ≥ 0.053) and MG (p ≥ 0.756) for both CDFI-VI and Angio-PL.U.S.-VI. Only VI measures for the non-dominant BB demonstrated significant intra-limb difference between techniques (p = 0.002). A significant %SSD between techniques was observed for BB (p = 0.022) but not MG (p = 0.225). Strong to very strong correlations were observed between CDFI-VI and Angio-PL.U.S.-VI across all muscles (ρ = 0.616-0.814, p ≤ 0.001)., Conclusion: Ultrafast Angio-PL.U.S. and conventional ultrasound imaging techniques were comparable when used in conjunction with the VI for quantifying resting intramuscular blood flow. Angio-PL.U.S. appeared to be more sensitive in detecting bilateral disparities in upper extremity muscles. However, further research is needed to validate these findings and investigate the potential clinical utility of this technique for characterizing disease progression in populations with global or unilateral musculoskeletal tissue alterations., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained on the day of the initial functional assessment prior to data collection. The study was approved by the Human Subjects Ethics Sub-committee of the Hong Kong Polytechnic University on April 10, 2018 (HSEARS20171212003). All procedures were conducted in accordance with the Helsinki Declaration for human experiments and reported in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Disturbed flow generates oscillatory shear stress (OSS), which in turn leads to endothelial inflammation and atherosclerosis. Piezo1, a biomechanical force sensor, plays a crucial role in the cardiovascular system. However, the specific role of Piezo1 in atherosclerosis remains to be fully elucidated., Methods and Results: We detected the expression of Piezo1 in atherosclerotic mice and endothelial cells from regions with disturbed blood flow. The pharmacological inhibitor Piezo1 inhibitor (GsMTx4) was used to evaluate the impact of Piezo1 on plaque progression and endothelial inflammation. We examined Piezo1's direct response to OSS in vitro and its effects on endothelial inflammation. Furthermore, mechanistic studies were conducted to explore the potential molecular cascade through which Piezo1 mediates endothelial inflammation in response to OSS. Our findings revealed the upregulation of Piezo1 in apoE-/- (apolipoprotein E) atherosclerotic mice, which is associated with disturbed flow. Treatment with GsMTx4 not only delayed plaque progression but also mitigated endothelial inflammation in both chronic and disturbed flow-induced atherosclerosis. Piezo1 was shown to facilitate calcium ions (Ca 2 + ) influx in response to OSS, thereby activating endothelial inflammation. This inflammatory response was attenuated in the absence of Piezo1. Additionally, we identified that under OSS, Piezo1 activates the Ca 2 + /CaM/CaMKII (calmodulin/calmodulin-dependent protein kinases Ⅱ) pathways, which subsequently stimulate downstream kinases FAK (focal adhesion kinase) and Src. This leads to the activation of the OSS-sensitive YAP (yes-associated protein), ultimately triggering endothelial inflammation., Conclusions: Our study highlights the key role of Piezo1 in atherosclerotic endothelial inflammation, proposing the Piezo1-Ca 2+ /CaM/CaMKII-FAK/Src-YAP axis as a previously unknown endothelial mechanotransduction pathway. Piezo1 is expected to become a potential therapeutic target for atherosclerosis and cardiovascular diseases.