Roy, Tuhin K.

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.

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. AbstractThe 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 () was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake () (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in between trials was related to the change in (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.

Arterial oxygen tension and oxyhemoglobin saturation ([Formula: see text]) decrease in parallel during hypoxia. Distinguishing between changes in oxygen tension and oxygen content as the relevant physiological stimulus for cardiorespiratory alterations remains challenging. To overcome this, we recruited nine individuals with hemoglobinopathy manifesting as high-affinity hemoglobin [HAH; partial pressure at 50% [Formula: see text] (P50) = 16 ± 0.4 mmHg] causing greater [Formula: see text] at a given oxygen partial pressure compared with control subjects ( n = 12, P50 = 26 ± 0.4 mmHg). We assessed ventilatory and cardiovascular responses to acute isocapnic hypoxia, iso-oxic hypercapnia, and 20 min of isocapnic hypoxia (arterial Po2 = 50 mmHg). Blood gas alterations were achieved with dynamic end-tidal forcing. When expressed as a function of the logarithm of oxygen partial pressure, ventilatory sensitivity to hypoxia was not different between groups. However, there was a significant difference when expressed as a function of [Formula: see text]. Conversely, the rise in heart rate was blunted in HAH subjects when expressed as a function of partial pressure but similar when expressed as a function of [Formula: see text]. Ventilatory sensitivity to hypercapnia was not different between groups. During sustained isocapnic hypoxia, the rise in minute ventilation was similar between groups; however, heart rate was significantly greater in the controls during 3 to 9 min of exposure. Our results support the notion that oxygen tension, not content, alters cellular Po2in the chemosensors and drives the hypoxic ventilatory response. Our study suggests that in addition to oxygen partial pressure, oxygen content may also influence the heart rate response to hypoxia.NEW & NOTEWORTHY We dissociated the effects of oxygen content and pressure of cardiorespiratory regulation studying individuals with high-affinity hemoglobin (HAH). During hypoxia, the ventilatory response, expressed as a function of oxygen tension, was similar between HAH variants and controls; however, the rise in heart rate was blunted in the variants. Our work supports the notion that the hypoxic ventilatory response is regulated by oxygen tension, whereas cardiovascular regulation may be influenced by arterial oxygen content and tension.

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 . 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. AbstractThe 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 ( = 0.25 L min−1, cardiac output = 5.70 L min−1) and during exercise ( = 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.

Epicardial pacing wires are routinely used to avoid hemodynamic instability due to perioperative arrhythmias after cardiac surgery. In rare cases, pacing wires themselves can be associated with potentially life-threatening complications. Herein, we present a novel case of hemorrhagic shock and hemoperitoneum after temporary epicardial pacing wire removal.

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.