Roy, Tuhin K

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.

AbstractOxygen 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 (V̇O2max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin‐oxygen affinity. However, the effect of such alterations on V̇O2max 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 V̇O2max 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 V̇O2max 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 V̇O2max at altitudes above ~4500 m.

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.

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. AbstractRecently, 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.

Abstract 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.

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.

A theoretical model of the pulmonary vasculature is used to predict the effects of vasoconstriction over specified ranges of vessel diameters on pulmonary vascular resistance (PVR). The model shows that observed levels of hypoxic vasoconstriction in terminal vessels cannot account for the elevation of PVR associated with hypoxic pulmonary vasoconstriction (HPV). Upstream signaling by conducted responses to engage constriction of arterioles, therefore, plays an essential role in the elevation of PVR during HPV.

Pulmonary oxygen uptake is affected by the transport characteristics of the alveolar‐capillary membrane as well as heterogeneity of pulmonary blood flow, both of which can limit the lung's capacity for oxygen transport as characterized by its effective diffusing capacity. In previous work, we showed that while under resting conditions the healthy lung has a high degree of tolerance for pulmonary flow heterogeneity, under conditions of exercise such flow heterogeneity can preclude the high levels of oxygen uptake necessary to meet tissue demand. The goal of the present study is to test the ability of hypoxic pulmonary vasoconstriction (HPV) to mitigate flow heterogeneity and enable adequate oxygen transport levels in the lung to meet tissue needs under conditions of exercise. A mathematical model of pulmonary oxygen uptake is used, in which 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 high degree of heterogeneity, we simulate flow regulation in the cases of rest and exercise by adjusting pulmonary flow resistance in each vessel in accordance with 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 capillary. The results show a reduction in the effective CV from a baseline of 2.73 to 1.83 under resting conditions and to 0.66 in the case of exercise. The stronger reduction in heterogeneity under conditions of exercise corresponds to the need for greater flow regulation to minimize heterogeneity under conditions of physiologic stress. The predicted level of heterogeneity in exercise is in general agreement with our previous prediction of the upper limit of CV consistent with the levels of oxygen uptake in literature data for exercising humans. The results demonstrate the essential role of HPV to regulate flow and minimize heterogeneity under conditions of exercise and highlight the need for a functional pulmonary flow regulation mechanism under stressful or pathophysiological conditions. Support or Funding Information Supported by NIH U01 HL133362. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Microvascular blood flow regulation has important implications for optimization of metabolism‐perfusion matching in physiological and pathophysiological conditions such as exercise and sepsis. The purpose of this theoretical study is to assess the impact of various regulatory factors on metabolism‐perfusion matching. A microvascular network model including myogenic, shear, and metabolic flow regulation was developed and utilized to obtain estimates of oxygen extraction under control conditions as compared to a 20% global increase in blood flow accompanied by a 50% increase in oxygen consumption. The exercise state was simulated with preserved flow regulation and sepsis was simulated with impaired metabolic flow regulation. For the values of parameters used, overall oxygen extraction was found to be 28% higher in exercise compared to control values as opposed to only 23% higher in sepsis. This study demonstrates the impact of impaired flow regulation on oxygen delivery and highlights microvascular perfusion abnormalities as a putative mechanism for organ failure in critically ill patients.

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 .