Portal Vein Doppler Is a Sensitive Marker for Evaluating Venous Congestion in End-Stage Kidney Disease.

INTRODUCTION: Determining ultrafiltration volume in patients undergoing intermittent hemodialysis (IHD) is an essential component in the assessment and management of volume status. Venous excess ultrasound (VExUS) is a novel tool used to quantify the severity of venous congestion at the bedside. Given the high prevalence of pulmonary hypertension in patients with end-stage kidney disease (ESKD), venous Doppler could represent a useful tool to monitor decongestion in these patients. METHODS: This is a prospective observational study conducted in ESKD patients who were admitted to the hospital requiring IHD and ultrafiltration. Inferior vena cava maximum diameter (IVCd), portal vein Doppler (PVD), and hepatic vein Doppler (HVD) were performed in all patients before and after a single IHD session. RESULTS: Forty-one patients were included. The prevalence of venous congestion was 88% based on IVCd and 63% based on portal vein pulsatility fraction (PVPF). Both mean IVCd and PVPF displayed a significant improvement after ultrafiltration. The percent decrease in PVPF was significantly larger than the percent decrease in IVCd. HVD alterations did not significantly improve after ultrafiltration. CONCLUSIONS: Our study revealed a high prevalence of venous congestion in hospitalized ESKD patients undergoing hemodialysis. After a single IHD session, there was a significant improvement in both IVCd and PVPF. HVD showed no significant improvement with one IHD session. PVPF changes were more sensitive than IVCd changes during volume removal. This study suggests that, due to its rapid response to volume removal, PVD, among the various components of the VExUS grading system, could be more effective in monitoring real-time decongestion in patients undergoing IHD.

tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice.

INTRODUCTION: Amyloid beta (Aß) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aß accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aß-induced neurovascular and cognitive dysfunction. METHODS: Tg2576 mice and wild-type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later. RESULTS: Treatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid. DISCUSSION: These findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution. HIGHLIGHTS: Amyloid beta (Aß) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aß. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aß and tPA reconstitution may be of therapeutic value.

Reliability and reproducibility of the venous excess ultrasound (VExUS) score, a multi-site prospective study: validating a novel ultrasound technique for comprehensive assessment of venous congestion.

Though the novel venous excess ultrasound (VExUS) score is increasingly used as a noninvasive means of venous congestion measurement, the inter-rater reliability (IRR), inter-user reproducibility (IUR), and utility of concurrent ECG have not been evaluated. We conducted a multicenter study of the IRR, IUR, and utility of ECG for VExUS interpretation between four attending physicians of diverse specialties, reporting the Kappa statistic (KS) and Intraclass Correlation Coefficient (ICC) for IRR and IUR for scans with and without ECG. Eighty-four paired VExUS exams from 42 patients, 60 of which had a concurrent ECG tracing, were interpreted. They showed substantial IRR, with a KS of 0.71 and ICC of 0.83 for the overall VExUS grade (p < 0.001), and IUR, with a KS 0.63 and ICC of 0.8. There was greater agreement among images with an ECG tracing. These results suggest that ECG-augmented VExUS may be a reliable and reproducible measure interpretable by clinicians with diverse backgrounds.

Unlocking the Potential of VExUS in Assessing Venous Congestion: The Art of Doing It Right.

BACKGROUND: Congestion, marked by elevated cardiac filling pressures and their repercussions, is a contributing factor to morbidity and mortality in heart failure and critical illness. Relying on traditional methods for bedside evaluation often leads to inadequate decongestion and increased hospital readmissions. Point-of-care ultrasound (POCUS), particularly multi-organ POCUS, including the Venous Excess Ultrasound (VExUS) score, offers a promising approach in this scenario. VExUS enables the quantification of systemic venous congestion, aiding in fluid overload states by assessing inferior vena cava and venous Doppler waveforms. SUMMARY: This comprehensive review delves into the latest developments in comprehending and evaluating congestion, shedding light on technical intricacies to enhance the effective application of VExUS. Recent studies emphasize the importance of evaluating signs of hemodynamic congestion before administering intravenous fluids, highlighting the concept of "fluid tolerance." Moreover, VExUS-guided decongestion significantly improves decongestion rates in acute decompensated heart failure patients with acute kidney injury. Newer studies also highlight the prognostic implications of VExUS in the general ICU cohorts not confining to cardiac surgery patients. However, performing VExUS without understanding technical pitfalls may lead to clinical errors. Technical considerations in performing VExUS include nuances related to inferior vena cava and internal jugular vein ultrasound and familiarity with Doppler principles, optimal settings, and artifacts. Additionally, local structural alterations such as those seen in liver and kidney disease impact Doppler waveforms, emphasizing the need for careful interpretation. KEY MESSAGE: Overall, VExUS presents a valuable tool for assessing congestion and guiding management, provided clinicians are familiar with its technical complexities and interpret findings judiciously.

Interaction of macro- and microvascular function underlies brachial artery flow-mediated dilation in humans.

Brachial artery flow-mediated dilation (BAFMD) is induced by hyperemic wall shear rate (WSR) following forearm ischemia. In older adults, there appears to be a reduced brachial hyperemic WSR and altered stimulus-response relationship compared with young adults. However, it is unclear if an altered forearm microvascular response to ischemia influences brachial hyperemic WSR in older adults. We determined associations between brachial hyperemic WSR and forearm skeletal muscle oxygen saturation in young and older adults. Healthy young (n = 17, 29 ± 7 yr) and older (n = 32, 65 ± 4 yr) adults participated in the study. BAFMD by a multigate spectral Doppler system and forearm skeletal muscle oxygen saturation by near-infrared spectroscopy were concurrently measured. When compared with the young, older adults showed reduced oxygen extraction kinetics (OE, 0.15 [0.12-0.17] vs. 0.09 [0.05-0.12]%s-1) and magnitude (So2deficit, 3,810 ± 1,420 vs. 2,723 ± 1,240%s) during ischemia, as well as oxygen resaturation kinetics (So2slope, 2.5 ± 0.7 vs. 1.7 ± 0.7%s-1) upon reperfusion (all P < 0.05). When OE in the young and So2slope in older adults were stratified by their median values, young adults with OE above the median had greater hyperemic WSR parameters compared with those below the median (P < 0.05), but So2slope in older adults did not show clear differences in hyperemic WSR parameters between those above/below the median. This study demonstrates that, in addition to a reduced microvascular response to ischemia, there may be a dissociation between microvascular response to ischemia and brachial hyperemic WSR in older adults, which may result in a further impairment of BAFMD in this cohort.NEW & NOTEWORTHY Microvascular response to ischemia and subsequent reperfusion is diminished in older adults compared with the young. Furthermore, there appears to be a dissociation between the microvascular response to ischemia and brachial hyperemic WSR in older adults, which may further disturb the BAFMD process in this cohort. A reduced BAFMD in older adults may be a result of multiple alterations occurring both at macro- and microcirculation.

Translational Research of the Acute Effects of Negative Emotions on Vascular Endothelial Health: Findings From a Randomized Controlled Study.

BACKGROUND: Provoked anger is associated with an increased risk of cardiovascular disease events. The underlying mechanism linking provoked anger as well as other core negative emotions including anxiety and sadness to cardiovascular disease remain unknown. The study objective was to examine the acute effects of provoked anger, and secondarily, anxiety and sadness on endothelial cell health. METHODS AND RESULTS: Apparently healthy adult participants (n=280) were randomized to an 8-minute anger recall task, a depressed mood recall task, an anxiety recall task, or an emotionally neutral condition. Pre-/post-assessments of endothelial health including endothelium-dependent vasodilation (reactive hyperemia index), circulating endothelial cell-derived microparticles (CD62E+, CD31+/CD42-, and CD31+/Annexin V+) and circulating bone marrow-derived endothelial progenitor cells (CD34+/CD133+/kinase insert domain receptor+ endothelial progenitor cells and CD34+/kinase insert domain receptor+ endothelial progenitor cells) were measured. There was a group×time interaction for the anger versus neutral condition on the change in reactive hyperemia index score from baseline to 40 minutes (P=0.007) with a mean±SD change in reactive hyperemia index score of 0.20±0.67 and 0.50±0.60 in the anger and neutral conditions, respectively. For the change in reactive hyperemia index score, the anxiety versus neutral condition group by time interaction approached but did not reach statistical significance (P=0.054), and the sadness versus neutral condition group by time interaction was not statistically significant (P=0.160). There were no consistent statistically significant group×time interactions for the anger, anxiety, and sadness versus neutral condition on endothelial cell-derived microparticles and endothelial progenitor cells from baseline to 40 minutes. CONCLUSIONS: In this randomized controlled experimental study, a brief provocation of anger adversely affected endothelial cell health by impairing endothelium-dependent vasodilation.

Differential Effect of Aortic Valve Replacement for Severe Aortic Stenosis on Hyperemic and Resting Epicardial Coronary Pressure Indices.

BACKGROUND: Coronary pressure indices to assess coronary artery disease are currently underused in patients with aortic stenosis due to many potential physiological effects that might hinder their interpretation. Studies with varying sample sizes have provided us with conflicting results on the effect of transcatheter aortic valve replacement (TAVR) on these indices. The aim of this meta-analysis was to study immediate and long-term effects of TAVR on fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs). METHODS AND RESULTS: Lesion-specific coronary pressure data were extracted from 6 studies, resulting in 147 lesions for immediate change in FFR analysis and 105 for NHPR analysis. To investigate the long-term changes, 93 lesions for FFR analysis and 68 for NHPR analysis were found. Lesion data were pooled and compared with paired t tests. Immediately after TAVR, FFR decreased significantly (-0.0130±0.0406 SD, P: 0.0002) while NHPR remained stable (0.0003±0.0675, P: 0.9675). Long-term after TAVR, FFR decreased significantly (-0.0230±0.0747, P: 0.0038) while NHPR increased nonsignificantly (0.0166±0.0699, P: 0.0543). When only borderline NHPR lesions were considered, this increase became significant (0.0249±0.0441, P: 0.0015). Sensitivity analysis confirmed our results in borderline lesions. CONCLUSIONS: TAVR resulted in small significant, but opposite, changes in FFR and NHPR. Using the standard cut-offs in patients with severe aortic stenosis, FFR might underestimate the physiological significance of a coronary lesion while NHPRs might overestimate its significance. The described changes only play a clinically relevant role in borderline lesions. Therefore, even in patients with aortic stenosis, an overtly positive or negative physiological assessment can be trusted.

Non-Invasive Monitoring of Microvascular Oxygenation and Reactive Hyperemia using Hybrid, Near-Infrared Diffuse Optical Spectroscopy for Critical Care.

The detection of levels of impairment in microvascular oxygen consumption and reactive hyperemia is vital in critical care. However, there are no practical means for a robust and quantitative evaluation. This paper describes a protocol to evaluate these impairments using a hybrid near-infrared diffuse optical device. The device contains modules for near-infrared time-resolved and diffuse correlation spectroscopies and pulse-oximetry. These modules allow the non-invasive, continuous, and real-time measurement of the absolute, microvascular blood/tissue oxygen saturation (StO2) and the blood flow index (BFI) along with the peripheral arterial oxygen saturation (SpO2). This device uses an integrated, computer-controlled tourniquet system to execute a standardized protocol with optical data acquisition from the brachioradialis muscle. The standardized vascular occlusion test (VOT) takes care of the variations in the occlusion duration and pressure reported in the literature, while the automation minimizes inter-operator differences. The protocol we describe focuses on a 3-min occlusion period but the details described in this paper can readily be adapted to other durations and cuff pressures, as well as other muscles. The inclusion of an extended baseline and post-occlusion recovery period measurement allows the quantification of the baseline values for all the parameters and the blood/tissue deoxygenation rate that corresponds to the metabolic rate of oxygen consumption. Once the cuff is released, we characterize the tissue reoxygenation rate, magnitude, and duration of the hyperemic response in BFI and StO2. These latter parameters correspond to the quantification of the reactive hyperemia, which provides information about the endothelial function. Furthermore, the above-mentioned measurements of the absolute concentration of oxygenated and deoxygenated hemoglobin, BFI, the derived metabolic rate of oxygen consumption, StO2, and SpO2 provide a yet-to-be-explored rich data set that can exhibit disease severity, personalized therapeutics, and management interventions.

Associations of between- and within-day patterns of physical activity accumulation with arterial stiffness and indices of microvascular health-Evidence from The Maastricht study.

While physical activity (PA) is understood to promote vascular health, little is known about whether the daily and weekly patterns of PA accumulation associate with vascular health. Accelerometer-derived (activPAL3) 6- or 7-day stepping was analyzed for 6430 participants in The Maastricht Study (50.4% women; 22.4% Type 2 diabetes mellitus (T2DM)). Multivariable regression models examined associations between stepping metrics (average step count, and time spent slower and faster paced stepping) with arterial stiffness (measured as carotid-femoral pulse wave velocity (cfPWV)), and several indices of microvascular health (heat-induced skin hyperemia, retinal vessel reactivity and diameter), adjusting for confounders and moderators. PA pattern metrics were added to the regression models to identify associations with vascular health beyond that of stepping metrics. Analyses were stratified by T2DM status if an interaction effect was present. Average step count and time spent faster paced stepping was associated with better vascular health, and the association was stronger in those with compared to those without T2DM. In fully adjusted models a higher step count inter-daily stability was associated with a higher (worse) cfPWV in those without T2DM (std ß = 0.04, p = 0.007) and retinal venular diameter in the whole cohort (std ß = 0.07, p = 0.002). A higher within-day variability in faster paced stepping was associated with a lower (worse) heat-induced skin hyperemia in those with T2DM (std ß = -0.31, p = 0.008). Above and beyond PA volume, the daily and weekly patterns in which PA was accumulated were additionally associated with improved macro- and microvascular health, which may have implications for the prevention of vascular disease.

Optimization of Absolute Coronary Blood Flow Measurements to Assess Microvascular Function: In Vivo Validation of Hyperemia and Higher Infusion Speeds.

BACKGROUND: Reliable assessment of coronary microvascular function is essential. Techniques to measure absolute coronary blood flow are promising but need validation. The objectives of this study were: first, to validate the potential of saline infusion to generate maximum hyperemia in vivo. Second, to validate absolute coronary blood flow measured with continuous coronary thermodilution at high (40-50 mL/min) infusion speeds and asses its safety. METHODS: Fourteen closed-chest sheep underwent absolute coronary blood flow measurements with increasing saline infusion speeds at different dosages under general anesthesia. An additional 7 open-chest sheep underwent these measurements with epicardial Doppler flow probes. Coronary flows were compared with reactive hyperemia after 45 s of coronary occlusion. RESULTS: Twenty milliliters per minute of saline infusion induced a significantly lower hyperemic coronary flow (140 versus 191 mL/min; P=0.0165), lower coronary flow reserve (1.82 versus 3.21; P≤0.0001), and higher coronary resistance (655 versus 422 woods units; P=0.0053) than coronary occlusion. On the other hand, 30 mL/min of saline infusion resulted in hyperemic coronary flow (196 versus 192 mL/min; P=0.8292), coronary flow reserve (2.77 versus 3.21; P=0.1107), and coronary resistance (415 versus 422 woods units; P=0.9181) that were not different from coronary occlusion. Hyperemic coronary flow was 40.7% with 5 mL/min, 40.8% with 10 mL/min, 73.1% with 20 mL/min, 102.3% with 30 mL/min, 99.0% with 40 mL/min, and 98.0% with 50 mL/min of saline infusion when compared with postocclusive hyperemic flow. There was a significant bias toward flow overestimation (Bland-Altman: bias±SD, -73.09±30.52; 95% limits of agreement, -132.9 to -13.27) with 40 to 50 mL/min of saline. Occasionally, ischemic changes resulted in ventricular fibrillation (9.5% with 50 mL/min) at higher infusion rates. CONCLUSIONS: Continuous saline infusion of 30 mL/min but not 20 mL/min induced maximal hyperemia. Absolute coronary blood flow measured with saline infusion speeds of 40 to 50 mL/min was not accurate and not safe.

Exercise-induced calf muscle hyperemia quantified with dynamic blood oxygen level-dependent (BOLD) imaging.

Muscle hyperemia in exercise is usually the combined result of increased cardiac output and local muscle vasodilation, with the latter reflecting muscle's capacity for increased blood perfusion to support exercise. In this study, we aim to quantify muscle's vasodilation capability with dynamic BOLD imaging. A deoxyhemoglobin-kinetics model is proposed to analyze dynamic BOLD signals acquired during exercise recovery, deriving a hyperemia index (HI) for a muscle group of interest. We demonstrated the method's validity with calf muscles of healthy subjects who performed plantar flexion for muscle stimulation. In a test with exercise load incrementally increasing from 0 to 16 lbs., gastrocnemius HI showed considerable variance among the 4 subjects, but with a consistent trend, i.e. low at light load (e.g. 0-6 lbs) and linearly increasing at heavy load. The high variability among different subjects was confirmed with the other 10 subjects who exercised with a same moderate load of 8 lbs., with coefficient of variance among subjects' medial gastrocnemius 87.8%, lateral gastrocnemius 111.8% and soleus 132.3%. These findings align with the fact that intensive exercise induces high muscle hyperemia, but a comparison among different subjects is hard to make, presumably due to the subjects' different rate of oxygen utilization. For the same 10 subjects who exercised with load of 8 lbs., we also performed dynamic contrast enhanced (DCE) MRI to measure muscle perfusion (F). With a moderate correlation of 0.654, HI and F displayed three distinctive responses of calf muscles: soleus of all the subjects were in the cluster of low F and low HI, and gastrocnemius of most subjects had high F and either low or high HI. This finding suggests that parameter F encapsulates blood flow through vessels of all sizes, but BOLD-derived HI focuses on capillary flow and therefore is a more specific indicator of muscle vasodilation. In conclusion, the proposed hyperemia index has the potential of quantitatively assessing muscle vasodilation induced with exercise.

Near-Infrared Spectroscopy During Reactive Hyperemia for the Assessment of Lower Limb Vascular Function.

Vascular diseases of the lower limb contribute substantially to the global burden of cardiovascular disease and comorbidities such as diabetes. Importantly, microvascular dysfunction can occur prior to, or alongside, macrovascular pathology, and both potentially contribute to patient symptoms and disease burden. Here, we describe a non-invasive approach using near-infrared spectroscopy (NIRS) during reactive hyperemia, which provides a standardized assessment of lower limb vascular (dys)function and a potential method to evaluate the efficacy of therapeutic interventions. Unlike alternative methods, such as contrast-enhanced ultrasound, this approach does not require venous access or sophisticated image analysis, and it is inexpensive and less operator-dependent. This description of the NIRS method includes representative results and standard terminology alongside the discussion of measurement considerations, limitations, and alternative methods. Future application of this work will improve standardization of vascular research design, data collection procedures, and harmonized reporting, thereby enhancing translational research outcomes in the areas of lower limb vascular (dys)function, disease, and treatment.