Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis.

The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome. While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids. This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology

Estimated central blood volume in cirrhosis

The estimated central blood volume (i.e., blood volume in the heart cavities, lungs and central arterial tree) was determined by multiplying cardiac output by circulatory mean transit time in 19 patients with cirrhosis and compared with sympathetic nervous activity and circulating level of atrial natriuretic factor. Arterial norepinephrine level, an index of overall sympathetic nervous activity (3.08 nmol/L in patients vs. 1.36 nmol/L in controls; p < 0.01) was negatively correlated (r = -0.54, p < 0.01) with estimated central blood volume (mean = 23 ml/kg in patients vs. 27 ml/kg in controls; p < 0.05). Similarly, renal venous norepinephrine level (an index of renal sympathetic tone; 4.26 nmol/L in patients vs. 1.78 nmol/L in controls; p < 0.01) was inversely correlated with estimated central blood volume (r = -0.53, n = 18, p < 0.02). No significant correlation could be established between arterial atrial natriuretic factor level (8.9 pmol/L in patients vs. 9.6 pmol/L in controls; not significant) and estimated central blood volume. Hemodynamic values were subsequently modified with oral propranolol (80 mg). During -adrenergic blockade, the mean estimated central blood volume was not altered significantly, except in six patients who exhibited decreases in mean arterial blood pressure (85 to 69 mm Hg; n = 6) and decreases in mean estimated central blood volume (23.2 to 20.6 ml/kg; n = 6, p < 0.05). Slight increases were observed in mean right atrial pressure (2.2 to 3.7 mm Hg; n = 14, p < 0.05); this change was positively correlated with the change in estimated central blood volume (r = 0.44, n = 14, p = 0.06). In conclusion, reduced estimated central blood volume probably unloads volume receptors and baroreceptors, thus provoking enhanced overall and renal sympathetic nervous activity and thereby contributing to increased water and salt retention in cirrhosis. During -adrenergic blockade estimated central blood volume changes correlated with alterations in preload and afterload. These findings indicate that central circulatory and arterial underfilling is a key element of the hemodynamic derangement observed in cirrhosis

Topical Menthol, Ice, Peripheral Blood Flow, and Perceived Discomfort

Context : Injury management commonly includes decreasing arterial blood flow to the affected site in an attempt to reduce microvascular blood flow and edema and limit the induction of inflammation. Applied separately, ice and menthol gel decrease arterial blood flow, but the combined effects of ice and menthol gel on arterial blood flow are unknown. Objectives : To compare radial artery blood flow, arterial diameter, and perceived discomfort before and after the application of 1 of 4 treatment conditions. Design : Experimental crossover design. Setting : Clinical laboratory. Participants or Other Participants : Ten healthy men, 9 healthy women (mean age = 25.68 years, mean height = 1.73 m, mean weight = 76.73 kg). Intervention(s) : Four treatment conditions were randomly applied for 20 minutes to the right forearm of participants on 4 different days separated by at least 24 hours: (1) 3.5 mL menthol gel, (2) 0.5 kg of crushed ice, (3) 3.5 mL of menthol gel and 0.5 kg of crushed ice, or (4) no treatment (control). Main Outcome Measure(s) : Using high-resolution ultrasound, we measured right radial artery diameter (cm) and blood flow (mL/min) every 5 minutes for 20 minutes after the treatment was applied. Discomfort with the treatment was documented using a 1-to-10 intensity scale. Results : Radial artery blood flow decreased (P \u3c .05) from baseline in the ice (−20% to −24%), menthol (−17% to −24%), and ice and menthol (−36% to −39%) treatments but not in the control (3% to 9%) at 5, 10, and 15 minutes. At 20 minutes after baseline, only the ice (−27%) and combined ice and menthol (−38%) treatments exhibited reductions in blood flow (P \u3c .05). Discomfort was less with menthol than with the ice treatment at 5, 10, and 20 minutes after application (P \u3c .05). Arterial diameter and heart rate did not change. Conclusions : The application of 3.5 mL of menthol was similar to the application of 0.5 kg of crushed ice in reducing peripheral blood flood. Combining crushed ice with menthol appeared to have an additive effect on reducing blood flow

Abnormal arterial-venous fusions and fate specification in mouse embryos lacking blood flow.

The functions of blood flow in the morphogenesis of mammalian arteries and veins are not well understood. We examined the development of the dorsal aorta (DA) and the cardinal vein (CV) in Ncx1 -/- mutants, which lack blood flow due to a deficiency in a sodium calcium ion exchanger expressed specifically in the heart. The mutant DA and CV were abnormally connected. The endothelium of the Ncx1 -/- mutant DA lacked normal expression of the arterial markers ephrin-B2 and Connexin-40. Notch1 activation, known to promote arterial specification, was decreased in mutant DA endothelial cells (ECs), which ectopically expressed the venous marker Coup-TFII. These findings suggest that flow has essential functions in the DA by promoting arterial and suppressing venous marker expression. In contrast, flow plays a lesser role in the CV, because expression of arterial-venous markers in CV ECs was not as dramatically affected in Ncx1 -/- mutants. We propose a molecular mechanism by which blood flow mediates DA and CV morphogenesis, by regulating arterial-venous specification of DA ECs to ensure proper separation of the developing DA and CV

Blood flow-induced Notch activation and endothelial migration enable vascular remodeling in zebrafish embryos.

Arteries and veins are formed independently by different types of endothelial cells (ECs). In vascular remodeling, arteries and veins become connected and some arteries become veins. It is unclear how ECs in transforming vessels change their type and how fates of individual vessels are determined. In embryonic zebrafish trunk, vascular remodeling transforms arterial intersegmental vessels (ISVs) into a functional network of arteries and veins. Here we find that, once an ISV is connected to venous circulation, venous blood flow promotes upstream migration of ECs that results in displacement of arterial ECs by venous ECs, completing the transformation of this ISV into a vein without trans-differentiation of ECs. Arterial blood flow initiated in two neighboring ISVs prevents their transformation into veins by activating Notch signaling in ECs. Together, different responses of ECs to arterial and venous blood flow lead to formation of a balanced network with equal numbers of arteries and veins

Functional optimization of the arterial network

We build an evolutionary scenario that explains how some crucial physiological constraints in the arterial network of mammals - i.e. hematocrit, vessels diameters and arterial pressure drops - could have been selected by evolution. We propose that the arterial network evolved while being constrained by its function as an organ. To support this hypothesis, we focus our study on one of the main function of blood network: oxygen supply to the organs. We consider an idealized organ with a given oxygen need and we optimize blood network geometry and hematocrit with the constraint that it must fulfill the organ oxygen need. Our model accounts for the non-Newtonian behavior of blood, its maintenance cost and F\aa hr\ae us effects (decrease in average concentration of red blood cells as the vessel diameters decrease). We show that the mean shear rates (relative velocities of fluid layers) in the tree vessels follow a scaling law related to the multi-scale property of the tree network, and we show that this scaling law drives the behavior of the optimal hematocrit in the tree. We apply our scenario to physiological data and reach results fully compatible with the physiology: we found an optimal hematocrit of 0.43 and an optimal ratio for diameter decrease of about 0.79. Moreover our results show that pressure drops in the arterial network should be regulated in order for oxygen supply to remain optimal, suggesting that the amplitude of the arterial pressure drop may have co-evolved with oxygen needs.Comment: Shorter version, misspelling correctio

Determining arterial blood velocity using MAUI software from recorded doppler ultrasound videos

Objectives: The purpose of this study was to investigate the repeatability and reproducibility of a new software, developed to provide measurements of arterial blood velocity from recorded Doppler ultrasound videos. Methods: The “Measurements from Arterial Ultrasound Imaging” (MAUI) software (Hedgehog Medical Inc.), developed for the measurement of arterial dimensions, has been expanded to measure the blood velocity from ultrasound videos. MAUI uses an adaptive based segmentation and intelligent outlier removal image analysis method to determine the instantaneous peak velocity in the positive and negative directions and the intensity weighted mean of the signal. Three recorded videos of popliteal arterial velocity were used to evaluate the reproducibility and repeatability of MAUI. For this assessment, two investigators (E1 and E2) each performed 10 measurements of the three test videos using MAUI. Results: MAUI provided blood velocity measurements (cm/s) for each frame of each video. The ten measurements made by E1 and E2 were averaged and are listed below (mean ± SD).Video # Velocity Measure E1 E21 Positive Envelope 27.84 ± 0.15 27.31 ± 0.28 Negative Envelope -13.99 ± 0.28 -13.68 ± 0.19 Mean Signal 13.80 ± 0.24 13.81 ± 0.102 Positive Envelope 42.30 ± 0.13 42.34 ± 0.33 Negative Envelope -11.51 ± 0.28 -11.53 ± 0.24 Mean Signal 29.69 ± 0.02 29.08 ± 0.363 Positive Envelope 53.48 ± 0.11 53.54 ± 0.20 Negative Envelope -13.66 ± 0.10 -13.40 ± 0.21 Mean Signal 38.60 ± 0.12 38.47 ± 0.17Conclusion: Preliminary assessments suggest that MAUI is a viable method for the measurement of blood velocity from recorded Doppler ultrasound video with high repeatability and low interrater variability. In future, measurements of velocity may be combined with existing continuous measurements of arterial diameter for the calculation of blood flow and assessments of vascular health and disease.<br/