Attenuated cardiac autonomic function in humans with high-affinity hemoglobin and compensatory polycythemia.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15-20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

Muscle oxygenation during normoxic and hypoxic cycling exercise in humans with high-affinity haemoglobin.

NEW FINDINGS: What is the central question of this study? Do humans with high-affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near-infrared spectroscopy-derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. ABSTRACT: Recently, researchers in our laboratory have shown that humans with genetic mutations resulting in high-affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal-affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near-infrared spectroscopy-derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal-affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

Effects of impaired microvascular flow regulation on metabolism-perfusion matching and organ function.

Impaired tissue oxygen delivery is a major cause of organ damage and failure in critically ill patients, which can occur even when systemic parameters, including cardiac output and arterial hemoglobin saturation, are close to normal. This review addresses oxygen transport mechanisms at the microcirculatory scale, and how hypoxia may occur in spite of adequate convective oxygen supply. The structure of the microcirculation is intrinsically heterogeneous, with wide variations in vessel diameters and flow pathway lengths, and consequently also in blood flow rates and oxygen levels. The dynamic processes of structural adaptation and flow regulation continually adjust microvessel diameters to compensate for heterogeneity, redistributing flow according to metabolic needs to ensure adequate tissue oxygenation. A key role in flow regulation is played by conducted responses, which are generated and propagated by endothelial cells and signal upstream arterioles to dilate in response to local hypoxia. Several pathophysiological conditions can impair local flow regulation, causing hypoxia and tissue damage leading to organ failure. Therapeutic measures targeted to systemic parameters may not address or may even worsen tissue oxygenation at the microvascular level. Restoration of tissue oxygenation in critically ill patients may depend on restoration of endothelial cell function, including conducted responses.

Shear wave dispersion analysis of incompressible waveguides.

A suite of methodologies is presented to compute shear wave dispersion in incompressible waveguides encountered in biomedical imaging; plate, tube, and general prismatic waveguides, all immersed in an incompressible fluid, are considered in this effort. The developed approaches are based on semi-analytical finite element methods in the frequency domain with a specific focus on the complexities associated with the incompressibility of the solid media as well as the simplification facilitated by the incompressibility of the surrounding fluid. The proposed techniques use the traditional idea of selective reduced integration for the solid medium and the more recent idea of perfectly matched discrete layers for the surrounding fluid. Also, used is the recently developed complex-length finite element method for platelike structures. Several numerical examples are presented to illustrate the practicality and effectiveness of the developed techniques in computing shear wave dispersion in a variety of waveguides.

Influence of high affinity haemoglobin on the response to normoxic and hypoxic exercise.

KEY POINTS: Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange. ABSTRACT: The longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P50  = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P50  = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end-exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects' oxyhaemoglobin saturation ( Sa,O2 ) was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake ( V̇O2max ) (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in V̇O2max between trials was related to the change in SaO2 (r = -0.75, p < 0.0001). Compared to normoxia, the controls' alveolar-to-arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia.

Modelling the relationships between haemoglobin oxygen affinity and the oxygen cascade in humans.

KEY POINTS: Haemoglobin affinity is an integral concept in exercise physiology that impacts oxygen uptake, delivery and consumption. How chronic alterations in haemoglobin affinity impact physiology is unknown. Using human haemoglobin variants, we demonstrate that the affinity of haemoglobin for oxygen is highly correlated with haemoglobin concentration. Using the Fick equation, we model how altered haemoglobin affinity and the associated haemoglobin concentration influences oxygen consumption at rest and during exercise via alterations in cardiac output and mixed-venous PO2 . The combination of low oxygen affinity haemoglobin and reduced haemoglobin concentration seen in vivo may be unable to support oxygen uptake during moderate or heavy exercise. ABSTRACT: The physiological implications, with regard to exercise, of altered haemoglobin affinity for oxygen are not fully understood. Data from the Mayo Clinic Laboratories database of rare human haemoglobin variants reveal a strong inverse correlation (r = -0.82) between blood haemoglobin concentration and P50 , an index of oxygen affinity [Hb = -0.3135(P50 ) + 23.636]. In the present study, observed P50 values for high, normal and low oxygen-affinity haemoglobin variants (13, 26 and 39 mmHg) and corresponding haemoglobin concentrations (19.5, 15.5 and 11.4 g dL-1 respectively) are used to model oxygen consumption as a fraction of delivery at rest ( V̇O2  = 0.25 L min-1 , cardiac output = 5.70 L min-1 ) and during exercise ( V̇O2  = 2.75 L min-1 , cardiac output = 18.9 l min-1 ). With high-affinity haemoglobin, the model shows that normal levels of oxygen consumption can be achieved at rest and during exercise at the assumed cardiac output levels, with reduced oxygen extraction both at rest (16.8% high affinity vs. 21.7% normal) and during exercise (55.8% high affinity vs. 72.2% normal). With low-affinity haemoglobin, which predicts low haemoglobin concentration, oxygen consumption at rest can be sustained with the assumed cardiac output, with increased oxygen extraction (31.1% low affinity vs. 21.7% normal). However, exercise at 2.75 l min-1 cannot be achieved with the assumed cardiac output, even with 100% oxygen extraction. In conclusion, the model indicates chronic alterations in P50 associate directly with Hb concentration, highlighting that human Hb variants can serve as 'experiments of nature' to address fundamental hypotheses on oxygen transport and exercise.

Generalized Supersoft Supersymmetry Breaking and a Solution to the µ Problem.

We propose the framework generalized supersoft supersymmetry breaking. "Supersoft" models, with D-type supersymmetry breaking and heavy Dirac gauginos, are considerably less constrained by the LHC searches than the well studied MSSM. These models also ameliorate the supersymmetric flavor and CP problems. However, previously considered mechanisms for obtaining a natural size Higgsino mass parameter (namely, µ) in supersoft models have been relatively complicated and contrived. Obtaining a 125 GeV for the mass of the lightest Higgs boson has also been difficult. Additional issues with the supersoft scenario arise from the fact that these models contain new scalars in the adjoint representation of the standard model, which may obtain negative squared-masses, breaking color and generating too large a T parameter. In this Letter, we introduce new operators into supersoft models which can potentially solve all these issues. A novel feature of this framework is that the new µ term can give unequal masses to the up and down type Higgs fields, and the Higgsinos can be much heavier than the Higgs boson without fine-tuning. However, unequal Higgs and Higgsino masses also remove some attractive features of supersoft supersymmetry.

Theoretical analysis of the determinants of lung oxygen diffusing capacity.

The process of pulmonary oxygen uptake is analyzed to obtain an explicit equation for lung oxygen diffusing capacity in terms of hematocrit and pulmonary capillary diameter. An axisymmetric model with discrete cylindrical erythrocytes is used to represent radial diffusion of oxygen from alveoli through the alveolar-capillary membrane into pulmonary capillaries, through the plasma, and into erythrocytes. Analysis of unsteady diffusion due to the passage of the erythrocytes shows that transport of oxygen through the alveolar-capillary membrane occurs mainly in the regions adjacent to erythrocytes, and that oxygen transport through regions adjacent to plasma gaps can be neglected. The model leads to an explicit formula for diffusing capacity as a function of geometric and oxygen transport parameters. For normal hematocrit and a capillary diameter of 6.75 µm, the predicted diffusing capacity is 102 ml O2 min⁻¹ mmHg⁻¹. This value is 30-40% lower than values estimated previously by the morphometric method, which considers the total membrane area and the specific uptake rate of erythrocytes. Diffusing capacity is shown to increase with increasing hematocrit and decrease with increasing capillary diameter and increasing thickness of the membrane. Simulations of pulmonary oxygen uptake in humans under conditions of exercise or hypoxia based show closer agreement with experimental data than previous models, but still overestimate oxygen uptake. The remaining discrepancy may reflect effects of heterogeneity of perfusion and ventilation in the lung.

Attenuation of Nerve Agent Induced Neurodegenerative and Neuroinflammatory Changes in Rats with New Combination Treatment of Galantamine, Atropine and Midazolam.

Acute nerve agent exposure can kill a person within minutes or produce multiple neurotoxic effects and subsequent brain damage with potential long-term adverse outcomes. Recent abuse of nerve-agents on Syrian civilians, during Japan terrorist attacks, and personal assassinations in the UK, and Malaysia indicate their potential threat to world population. Existing nerve agent antidotes offer only incomplete protection especially, if the treatment is delayed. To develop the effective drugs, it is advantageous to elucidate the underlying mechanisms of nerve agent-induced multiple neurological impairments. This study aimed to investigate the molecular basis of neuroinflammation during nerve agent toxicity with focus on inflammasome-associated proteins and neurodegeneration. In rats, NOD-like receptor family pyrin domain containing 3 (NLRP3), and glial fibrillary acidic protein (GFAP) immunoreactivity levels were considerably increased in the hippocampus, piriform cortex, and amygdala areas after single subcutaneous soman exposure (90 µg/kg-1). Western analysis indicated a notable increase in the neuroinflammatory indicator proteins, high mobility group box 1 (HMGB1) and inducible nitric oxide synthase (iNOS) levels. The presence of fluorojade-C-stained degenerating neurons in distinct rat brain areas is indicating the neurodegeneration during nerve agent toxicity. Pre-treatment with galantamine (3 mg/kg, - 30 min) followed by post-treatment of atropine (10 mg/kg, i.m.) and midazolam (5 mg/kg, i.m.), has completely protected animals from death induced by supra-lethal dose of soman (2XLD50) and reduced the neuroinflammatory and neurodegenerative changes. Results highlight that this new prophylactic and therapeutic drug combination might be an effective treatment option for soldiers deployed in conflict areas and first responders dealing with accidental/deliberate release of nerve agents.

Designing an implementation strategy to increase health-related social needs screening: Applying the PRISM framework in a resource-limited clinical setting.

Despite growing acceptability of health-related social needs (HRSN) screening and increasing policy incentives for adoption, clinical implementation of HRSN screening remains low. HRSN screening has been particularly difficult for Community Health Centers (CHCs), which have limited resources to implement and sustain new workflows. While CHCs provide care to patients with disproportionately high levels of unmet social needs, identifying HRSN screening implementation strategies that take CHC-specific contexts into account remains elusive. This study uses the Practical Robust Implementation and Sustainability Model (PRISM) to design an implementation strategy accounting for the unique context of CHCs. We used Rapid Ethnographic Assessment observations and stakeholder focus groups to identify current workflow barriers and facilitators to HRSN screening, and to develop implementation strategies that include multi-level contexts and perspectives. We identified eight themes contributing to low screening implementation: perceived stigma around screening; need for community-based solutions; re-confirming organizational priorities and values; Electronic Medical Record (EMR) limitations; multi-tasking pressures limiting implementation; staff turnover; limited knowledge of regulatory requirements; and community resource availability for referral. Based on the themes, we identified implementation strategies including non-EMR data collection; integration into the workflow for multiple staff members; creation of new training and educational modules; and identification of peer champions for retraining in real time. Administrative requirements are necessary but not sufficient for implementation of HRSN screening in CHCs. Resource-constrained settings benefit from context-specific stakeholder engagement to improve implementation success. The use of PRISM ensured contextual factors were central to the implementation strategy design.

Health care systems are encouraged to screen for health-related social needs (HRSN), such as housing and food insecurity, yet it has been difficult to implement these new screening workflows. This is especially true for Community Health Centers (CHCs) that have limited resources to implement new workflows. Using a framework that accounts for the unique environment of CHCs, we observed current workflows and conducted focus groups to develop an implementation strategy to facilitate HRSN screening. The new strategy used paper-based workflows to facilitate patient participation and identified clinical champions to engage staff. While these findings are useful in CHCs that might not have sufficient resources to develop screening processes in the Electronic Medical Record, they are also applicable to other low-resourced settings that might want to include HRSNs in patient care, but do not have resources or staff to do it.

An empirical model for world record running speeds with distance, age, and sex: anaerobic and aerobic contributions to performance.

The objective of this study is to derive mathematical equations that closely describe published data on world record running speed as a function of distance, age, and sex. Running speed declines with increasing distance and age. Over long distances, where aerobic metabolism is dominant, speed declines in proportion to the logarithm of distance. Over short distances, anaerobic metabolism contributes significantly to performance, and speed is increased relative to the trend of the long-distance data. Equations are derived that explicitly represent these effects. The decline in speed with age is represented by an age-dependent multiplicative factor, which exhibits increasing sensitivity to age as age increases. Using these equations, data are analyzed separately for males and females, and close fits to published data are demonstrated, particularly for younger age groups. These equations provide insight into the contributions of aerobic and anaerobic components of metabolism to athletic performance and a framework for comparisons of performance across wide ranges of distance and age.NEW & NOTEWORTHY World record speeds at different distances for men and women in different age categories are used to develop a model to predict running performance as a function of race distance, age, and sex. This empirical model quantifies the decline in running speed with distance and age in a way that provides insight into the aerobic and anaerobic contributions to running speed and may help with developing training strategies for different age groups at various distances.

Jets and photons.

This Letter applies the concept of "jets," as constructed from calorimeter cell four-vectors, to jets composed (primarily) of photons (or leptons). Thus jets become a superset of both traditional objects such as QCD jets, photons, and electrons, and more unconventional objects such as photon jets and electron jets, defined as collinear photons and electrons, respectively. Since standard objects such as single photons become a subset of jets in this approach, standard jet substructure techniques are incorporated into the photon finder toolbox. Using a (reasonably) realistic calorimeter model we demonstrate that, for a single photon identification efficiency of 80% or above, the use of jet substructure techniques reduces the number of QCD jets faking photons by factors of 2.5 to 4. Depending on the topology of the photon jets, the substructure variables reduce the number of photon jets faking single photons by factors of 10 to 10(3) at a single photon identification efficiency of 80%.

Full waveform inversion for arterial viscoelasticity.

Objective. Arterial viscosity is emerging as an important biomarker, in addition to the widely used arterial elasticity. This paper presents an approach to estimate arterial viscoelasticity using shear wave elastography (SWE).Approach. While dispersion characteristics are often used to estimate elasticity from SWE data, they are not sufficiently sensitive to viscosity. Driven by this, we develop a full waveform inversion (FWI) methodology, based on directly matching predicted and measured wall velocity in space and time, to simultaneously estimate both elasticity and viscosity. Specifically, we propose to minimize an objective function capturing the correlation between measured and predicted responses of the anterior wall of the artery.Results. The objective function is shown to be well-behaving (generally convex), leading us to effectively use gradient optimization to invert for both elasticity and viscosity. The resulting methodology is verified with synthetic data polluted with noise, leading to the conclusion that the proposed FWI is effective in estimating arterial viscoelasticity.Significance. Accurate estimation of arterial viscoelasticity, not just elasticity, provides a more precise characterization of arterial mechanical properties, potentially leading to a better indicator of arterial health.

The dependence of maximum oxygen uptake and utilization (V̇O2 max) on hemoglobin-oxygen affinity and altitude.

Oxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum human capacity for oxygen uptake and utilization (V̇O2 max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin-oxygen affinity. However, the effect of such alterations on V̇O2 max at extreme altitudes remains largely unknown due to the rarity of mutations affecting hemoglobin-oxygen affinity. This work uses a mathematical model that couples pulmonary oxygen uptake with systemic oxygen utilization under conditions of high metabolic demand to investigate the effect of hemoglobin-oxygen affinity on V̇O2 max as a function of altitude. The model includes the effects of both diffusive and convective limitations on oxygen transport. Pulmonary oxygen uptake is calculated using a spatially-distributed model that accounts for the effects of hematocrit and hemoglobin-oxygen affinity. Systemic oxygen utilization is calculated assuming Michaelis-Menten kinetics. The pulmonary and systemic model components are solved iteratively to compute predicted arterial and venous oxygen levels. Values of V̇O2 max are predicted for several values of hemoglobin-oxygen affinity and hemoglobin concentration based on data from humans with hemoglobin mutations. The model predicts that increased hemoglobin-oxygen affinity leads to increased V̇O2 max at altitudes above ~4500 m.

Theoretical comparison of wall-derived and erythrocyte-derived mechanisms for metabolic flow regulation in heterogeneous microvascular networks.

The objective of this study is to compare the effectiveness of metabolic signals derived from erythrocytes and derived from the vessel wall for regulating blood flow in heterogeneous microvascular networks. A theoretical model is used to simulate blood flow, mass transport, and vascular responses. The model accounts for myogenic, shear-dependent, and metabolic flow regulation. Metabolic signals are assumed to be propagated upstream along vessel walls via a conducted response. Arteriolar tone is assumed to depend on the conducted metabolic signal as well as local wall shear stress and wall tension, and arteriolar diameters are calculated based on vascular smooth muscle mechanics. The model shows that under certain conditions metabolic regulation based on wall-derived signals can be more effective in matching perfusion to local oxygen demand relative to regulation based on erythrocyte-derived signals, resulting in higher extraction and lower oxygen deficit. The lower effectiveness of the erythrocyte-derived signal is shown to result in part from the unequal partition of hematocrit at diverging bifurcations, such that low-flow vessels tend to receive a reduced hematocrit and thereby experience a reduced erythrocyte-derived metabolic signal. The model simulations predict that metabolic signals independent of erythrocytes may play an important role in local metabolic regulation of vascular tone and flow distribution in heterogeneous microvessel networks.

Nondeterministic approach to tree-based jet substructure.

Jet substructure is typically studied using clustering algorithms, such as k(T), which arrange the jets' constituents into trees. Instead of considering a single tree per jet, we propose that multiple trees should be considered, weighted by an appropriate metric. Then each jet in each event produces a distribution for an observable, rather than a single value. Advantages of this approach include (1) observables have significantly increased statistical stability, and (2) new observables, such as the variance of the distribution, provide new handles for signal and background discrimination. For example, we find that employing a set of trees substantially reduces the observed fluctuations in the pruned mass distribution, enhancing the likelihood of new particle discovery for a given integrated luminosity. Furthermore, the resulting pruned mass distributions for (background) QCD jets are found to be substantially wider than that for (signal) jets with intrinsic mass scales, e.g., boosted W jets. A cut on this width yields a substantial enhancement in significance relative to a cut on the standard pruned jet mass alone. In particular the luminosity needed for a given significance requirement decreases by a factor of 2 relative to standard pruning.

Full wave simulation of arterial response under acoustic radiation force.

With the ultimate goal of estimating arterial viscoelasticity using shear wave elastography, this paper presents a practical methodology to simulate the response of a human carotid artery under acoustic radiation force (ARF). The artery is idealized as a nearly incompressible viscoelastic hollow cylinder submerged in incompressible, inviscid fluid. For this idealization, we develop a multi-step methodology for efficient computation of three-dimensional response under complex ARF excitation, while capturing the fluid-structure interaction between the arterial wall and the surrounding fluid. The specific steps include (a) performing dimensional reduction through semi-analytical finite element formulation, (b) efficient finite element discretization using traditional and recent techniques. The computational efficiency is further enhanced by utilizing (c) modal superposition, followed by, where appropriate, (d) impulse response function. In addition to developing the methodology, convergence analysis is performed for a typical arterial geometry, leading to recommendations on various discretization parameters. At the end, the computational effort is shown to be several orders of magnitude less than the traditional, fully three-dimensional analysis using finite element methods, leading to a practical yet accurate simulation of arterial response under ARF excitations.

Functional implications of microvascular heterogeneity for oxygen uptake and utilization.

In the vascular system, an extensive network structure provides convective and diffusive transport of oxygen to tissue. In the microcirculation, parameters describing network structure, blood flow, and oxygen transport are highly heterogeneous. This heterogeneity can strongly affect oxygen supply and organ function, including reduced oxygen uptake in the lung and decreased oxygen delivery to tissue. The causes of heterogeneity can be classified as extrinsic or intrinsic. Extrinsic heterogeneity refers to variations in oxygen demand in the systemic circulation or oxygen supply in the lungs. Intrinsic heterogeneity refers to structural heterogeneity due to stochastic growth of blood vessels and variability in flow pathways due to geometric constraints, and resulting variations in blood flow and hematocrit. Mechanisms have evolved to compensate for heterogeneity and thereby improve oxygen uptake in the lung and delivery to tissue. These mechanisms, which involve long-term structural adaptation and short-term flow regulation, depend on upstream responses conducted along vessel walls, and work to redistribute flow and maintain blood and tissue oxygenation. Mathematically, the variance of a functional quantity such as oxygen delivery that depends on two or more heterogeneous variables can be reduced if one of the underlying variables is controlled by an appropriate compensatory mechanism. Ineffective regulatory mechanisms can result in poor oxygen delivery even in the presence of adequate overall tissue perfusion. Restoration of endothelial function, and specifically conducted responses, should be considered when addressing tissue hypoxemia and organ failure in clinical settings.