Citations

The rate at which oxygen can be taken up into the bloodstream in the lung is a critical determinant of functional capacity, and can be affected by heterogeneity of pulmonary blood flow (leading to maldistribution and poor ventilation‐perfusion matching) as well as alterations in diffusing capacity. Under resting conditions, the high degree of reserve in the healthy lung leads to adequate oxygen uptake even in the face of increased heterogeneity or decreased diffusing capacity; under conditions of exercise, however, oxygen transport and utilization are contingent upon adequate lung function with relatively little reserve. A mathematical model of pulmonary oxygen uptake is used in this study to investigate the impact of pulmonary flow heterogeneity in exercise, which we characterize by the coefficient of variation (CV) of pulmonary capillary blood flow; under conditions of uniform alveolar ventilation, this is theoretically equivalent to impaired ventilation‐perfusion matching. We have previously demonstrated that any level of pulmonary heterogeneity up to a high degree (CV of approximately 3.0) is consistent with the observed level of arterial oxygen tension under resting conditions. We hypothesize that such high levels of heterogeneity would preclude the high oxygen uptake in the lung observed during exercise. In this study, literature data on humans under normoxic and hypoxic conditions was used to estimate the CV of pulmonary capillary blood flow under conditions of moderate and extreme exercise. With the assumption of a normal diffusing capacity, the best fit overall to aggregated data from five studies was found with a CV of 0.61. These results show that a high degree of pulmonary flow heterogeneity does not limit oxygen uptake at rest, but that in exercise much lower levels of heterogeneity are necessary to achieve observed oxygen fluxes. An important mechanism for reducing heterogeneity is flow regulation via hypoxic pulmonary vasoconstriction (HPV), which is activated at the low levels of venous oxygen tension in exercise. The results suggest that HPV plays an essential role in allowing high levels of pulmonary oxygen uptake in exercise. Support or Funding Information Supported by NIH U01 HL133362 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Postulated mechanisms for metabolic flow regulation are examined using a theoretical model to simulate blood flow, mass transport and vascular responses in heterogeneous microvascular networks. 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. In heterogeneous networks, unequal partition of hematocrit at diverging bifurcations can lead to low hematocrit in low‐flow vessels. If the metabolic signal is generated solely by an erythrocyte‐dependent mechanism, such vessels then experience a reduced metabolic signal and may constrict further, leading to further decreases in hematocrit and oxygen delivery. Inclusion of a metabolic signal dependent on oxygen levels at the vessel walls can prevent this effect. The different functional ranges of oxygen tension at which these signals operate suggest a role for both types of signals in flow regulation. Supported by NIH grant HL070657.

The process of pulmonary oxygen uptake is analyzed to obtain quantitative estimates of pulmonary diffusing capacity. An axisymmetric model is used to represent radial diffusion of oxygen from alveoli through the alveolar‐capillary membrane, through the plasma, and into the erythrocytes. Analysis of unsteady diffusion due to the passage of the discrete erythrocytes shows that the 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. Calculations are performed for a range of discharge hematocrit and capillary diameter values. A value of approximately 75 mlO 2 mmHg −1 min −1 is obtained for normal hematocrit, assuming a capillary diameter of 6.75 μm. This value is much lower than the estimates obtained previously by the morphometric method, which considers the total membrane area and the specific uptake rate of erythrocytes. Simulations of pulmonary oxygen uptake based on the new estimates of lung diffusing capacity are consistent with experimental data on oxygen uptake in exercise and hypoxia. Supported by NIH grant HL070657.

Microvascular blood flow regulation involves multiple mechanisms designed to maintain adequate perfusion under conditions of varying metabolic demand. The impact of various regulatory factors on metabolism‐perfusion matching was assessed using a heterogeneous microvascular network model that accounted for myogenic, shear, and metabolic flow regulation. Estimates of oxygen extraction under control conditions were compared to an increase in tissue oxygen consumption in combination with a reduction in perfusion. For the values of parameters used, overall oxygen extraction was increased by a factor of 7.19 with a tenfold increase in consumption and a factor of 1.47 when perfusion was reduced by 50%. Combining increased consumption with decreased flow resulted in an increase in extraction by a factor of 9.20 compared to control, suggesting that network regulatory capacity remained intact under these conditions. This has significant implications for the optimization of metabolism‐perfusion matching, since impairment of flow regulation under conditions of increased consumption and decreased perfusion can lead to microvascular perfusion heterogeneity and cause organ failure in critically ill patients.

A mathematical simulation of flow regulation is used to investigate the hypothesis that vasoconstriction due to sympathetic nerve activity (SNA) in smaller arterioles is inhibited by functional vasodilation at higher values of oxygen demand, termed functional sympatholysis. A network with 13 vessel compartments in series is used, each compartment representing different size ranges of arterioles and venules. The model includes 5 actively regulating arteriolar segments with diameters influenced by shear stress, wall tension, metabolic regulation, and SNA. Metabolic signals are assumed to be propagated upstream along vessel walls via a conducted response. We show that for appropriately chosen parameter values, the vasoconstriction due to SNA in feed arterioles overcomes metabolic vasodilation at higher oxygen demand, resulting in persistent vasoconstriction throughout the period of SNA. In smaller arterioles under similar conditions, however, the initial vasoconstriction with SNA is followed by partial relaxation, consistent with the experimentally observed phenomenon of sympathetic escape. This implies that metabolic responses can account for observed characteristics of functional sympatholysis, including the different responses of large and small arterioles. Grant Funding Source : Supported by NIH grant HL070657.

Abstract Arterial stiffness is an important biomarker for many cardiovascular diseases. Shear wave elastography is a recent technique aimed at estimating local arterial stiffness using guided wave inversion (GWI), i.e. matching the computed and measured wave dispersion. This paper develops and validates a new GWI approach by synthesizing various recent observations and algorithms: (a) refinements to signal processing to obtain more accurate experimental dispersion curves; (b) an efficient forward model to compute theoretical dispersion curves for immersed, incompressible cylindrical waveguides; (c) an optimization framework based on the recent observation that the measured dispersion curve is multimodal, i.e. it matches for not one but two different wave modes in two different frequency ranges. The resulting inversion approach is validated using extensive experimental data from rubber tube phantoms, not only for modulus estimation but also to simultaneously estimate modulus and wall thickness. The observations indicate that the modulus estimates are best performed with the information on wall thickness. The approach, which takes less than half a minute to run, is shown to be accurate, with the modulus estimated with less than 4% error for 70% of the experiments.

Shear Wave Elastography (SWE) has been used to estimate arterial stiffness, an important biomarker for early cardiovascular diseases. In arterial SWE, the carotid artery is excited with acoustic radiation force and the observed wave propagation characteristics are used to estimate the arterial stiffness. We present an efficient guided wave inversion procedure, where the elastic modulus of the arterial wall is estimated by matching wave dispersion from experiments and simulation. Central to the proposed approach is an efficient forward model that computes the dispersion relation for the incompressible, immersed cylindrical tube; the model achieves high efficiency by combining semi-analytical finite element methods, selective reduced integration, and perfectly matched discrete layers. We utilize this forward model in an optimization framework to develop a streamlined methodology to estimate the modulus of the arterial wall. In this talk, we present the formulation of the method as well as validation using phantom experiments on 10 rubber tubes (VytaFlex-10), followed by preliminary work on inverting for the viscoelastic modulus.

Abstract 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.

The ability of the lung to take up oxygen can be characterized by its effective diffusing capacity, which is determined by the transport characteristics of the alveolar‐capillary membrane as well as heterogeneity of pulmonary blood flow. At rest, the healthy lung has a high degree of tolerance for pulmonary flow heterogeneity, but under conditions of physiological stress such as exercise, oxygen uptake may be inadequate to satisfy tissue demand if flow is very heterogeneous. We previously used a mathematical model of pulmonary oxygen uptake to examine the ability of hypoxic pulmonary vasoconstriction (HPV) to mitigate flow heterogeneity. In the model, flow heterogeneity is characterized by the coefficient of variation (CV) of pulmonary capillary blood flow. Assuming an initial lognormal distribution of blood flow with a normal level of heterogeneity (CV = 1.66), we simulate flow regulation over a range of oxygen consumption from rest to maximal exercise by adjusting pulmonary flow resistance in each vessel in accordance with an HPV response curve obtained from previously published experimental data. The effect of HPV on vessel flow resistance is assumed to be characterized by a sigmoidal response dependent on the capillary oxygen tension, which is approximated as the mean of the venous and arterial values in each pulmonary capillary; its maximal sensitivity occurs at a stimulus oxygen tension of approximately 30 torr. The purpose of the present study was to determine whether altering the shape of the HPV response curve would result in an improvement in CV reduction. Altering the HPV by shifting the sigmoidal curve to the right by 10 or 20 torr worsened CV, extraction and total pulmonary vascular resistance (PVR). Similar detrimental results were obtained when the range of oxygen tensions over which HPV varied was expanded by a factor of two, increasing the oxygen tension at which the sensitivity of HPV to oxygen tension was maximal. On the other hand, shrinking the range of variation of the HPV curve by a factor of two neither improved nor significantly worsened the CV or extraction, and resulted in a PVR distribution similar to the case of the normal HPV curve. These results demonstrate that the observed shape of the HPV response tends to minimize heterogeneity of pulmonary flow under conditions of exercise. Support or Funding Information Supported by NIH U01 HL133362.